Prerpints.org logo
Preprint
Review

This version is not peer-reviewed.

Gammadelta T Cells in Autoinflammatory Diseases

Submitted:

19 January 2026

Posted:

20 January 2026

You are already at the latest version

Abstract
Autoinflammatory diseases are characterized by inappropriate activation of innate immunity resulting in excessive or persistent inflammation in the absence of infection. γδ T cells possess innate-like properties, including rapid responsiveness to stress-induced self-molecules, phosphoantigens, and inflammasome-derived cytokines, while retaining adaptive effector functions. Neutrophils and macrophages are well-established drivers of autoinflammatory disease, but increasing evidence implicates γδ T cells as key intermediaries, by linking innate immune activation to tissue-specific inflammatory pathology.Here we review evidence that in both monogenic and multifactorial autoinflammatory diseases—including, for example, familial Mediterranean fever, hyper- immunoglobulin (Ig) D syndrome, gout, Behçet’s disease, Still’s disease, atherosclerosis, and neurodegenerative disorders—γδ T cells display altered frequencies, activation states, cytokine polarization, and tissue recruitment. In inflammasome-driven diseases, skewing of γδ T cells toward interleukin (IL)-17 production has been observed, often accompanied by reduced interferon (IFN)-γ secretion, thereby amplifying neutrophilic inflammation and tissue damage. In other diseases, e.g Behcet`s disease, IFNg and tumor necrosis factor (TNF)a producton predominate. Transcriptomic and tissue-based analyses support the accumulation and functional specialization of γδ T cells at sites of sterile inflammation. Collectively, these findings position γδ T cells as central amplifiers and modulators of inappropriate innate immune activation in the context of autoinflammatory diseases. Improved understanding of γδ T cell subset-specific regulation may inform novel therapeutic strategies targeting autoinflammatory diseases.
Keywords: 
gammadelta T cells
;  
autoinflammatory disease
;  
interleukin-17
;  
inflammasome
;  
interferon-gamma
;  
familial Mediterranean fever
;  
Behcet’s disease
;  
atherosclerosis
;  
Alzheimer’s disease
;  
Parkinson’s disease
;  
interleukin-1beta
;  
T cells
;  
innate immunity
Subject: 
Biology and Life Sciences  -   Life Sciences

Inappropriate Innate Immunity Activation

Inappropriate activation of innate immunity refers to situations where first-line immune defenses are activated in the absence of appropriate triggers (i.e. infection, noxious chemicals or adaptive immune responses), or remain activated longer or more potently than required to restore homeostasis . This can cause significant tissue damage, acute or chronic inflammation and thus lead to systemic autoinflammatory diseases.
Autoinflammatory diseases may be classified according to the causative inflammatory pathway pathogenically involved [1]. The monogenic autoinflammatory disorders are divided into inflammasomopathies i.e. those caused by mutations in inflammasome components, IL-1–mediated syndromes, tumor necrosis factor (TNF)-related syndromes, interferonopathies and nuclear factor kappa B (NF-κB) or ubiquitin pathway disorders. Specific defects, such as ubiquitin pathway disorders, including the recently described vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS ) syndrome. In addition, deficiency of adenosine deaminase 2 (DADA2) and IL-18–mediated macrophage activation syndrome are also included within this spectrum,as is pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome caused by mutations in the PSTPIP1 gene [2,3,4].) Autoinflammatory diseases in which no single specific causative mutation has been identified, are defined as polygenic or multifactorial autoinflammatory diseases, and include the periodic fever syndromes periodic fever, aphthous stomatitis, pharyngitis, adenitis syndrome (PFAPA), adult-onset Still’s disease and systemic juvenile idiopathic arthritis (sJIA), neutrophilic diseases (Behçet’s disease (BD), Sweet syndrome, synovitis-acne-pustulosis-hyperostosis-osteitis syndrome (SAPHO) syndromes and hydradenitis supporativa) and crystal-induced autoinflammation (gout and pseudogout). Organ specific autoinflammatory conditions are also multifactorial since they may encompass metabolic, infectious, or autoimmune components, and include idiopathic recurrent pericarditis, Kawasaki disease, polyarteritis nodosa, as well as chronic diseases such as atherosclerosis and neurodegenerative diseases.

gd T Cells and the Autoinflammatory Response

The main cellular components of the autoinflammatory response are neutrophils and macrophages. Whereas neutrophils (discovered by Paul Ehrlich in 1879), and macrophages (discovered by Metchnikoff in 1882) are known as prime mediators of inflammation, the role of gd T cells, discovered more than a century later, in 1986, has only been addressed over the past several decades [5,6]. These cells, that originate from bone marrow derived precursors developing in the thymus in fetal and post natal life, express on their cell surface a T cell receptor (TCR) heterodimer encoded by the rearranging g and d TCR genes, and emerge from the thymus to populate lymphatic and non lymphatic niches [7]. As opposed to ab TCRs expressed on conventional CD4+ and CD8+ T cells, most gd T cells do not express CD4 or CD8 co-receptors, a feature commensurate with their ability to recognize antigens directly, in a manner independent of major histocompatibily complex (MHC) molecules, which are required for peptide-antigen presentation to ab TCRs [8]. gd T cells comprise 1-10% of all circulating T cells in human peripheral blood (PB), increasing to 30% during certain infections, but consist a higher percentage (up to 20% ) of intra epithelial T cells in the gut, and in the liver at homeostasis [9].
There are two major types of gd T cells in humans categorized on the basis of the type of TCR genes expressed on the cell surface. The first , which predominates in the circulation, comprising up to 50-70% of the gd T cells, express the Vg9 and Vd2 TCR genes (Vg9d2 cells) [9]. The second major subset, uses Vd1 and one of several Vg genes in the TCR, and are less numerous in the PB but exhibit marked tissue tropism, predominating in intra epithelial locations (Vd1+ gd T cells) [9]. A third relatively rare subset uses Vd3 with various Vg partners, and exhibits features similar to those of the Vd1+ subset [9].
gd T cells occupy a unique niche in immunology by straddling innate and adaptive immune responses, and their innate reactivities serve as a direct link to autoinflammatory responses. For example, the TCR of the vast majority of Vg9d2 cells, is selected very early in ontogeny for recognition of phospho- antigens, primarily (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP), expressed by pathogens [10]. During infections, HMBPP binds to the intracellular B30.2 domain of BTN3A1, a member of the butyrophilin (BTN) family of cell surface molecules which is ubiquitously expressed on many types of cells, including antigen presenting cells (APC) [11]. This results in linking of BTN3A1 to BTN2A1 and conformationally perturbed heterodimeric BTN3A1-BTN2A1 complexes on the cell surface membrane [11]. Specific sites of the extracellular domain of this novel structure are recognized by germline conserved motifs of Vg9 and by complementarity-determining region (CDR) 2 of Vd2 polypeptides of the Vg9d2 TCR, driving Vg9d2 T cell activation to secrete inflammatory cytokines, primarily IFNg and TNFa [9]. Thus, the predominant Vg9d2 TCR is an innate receptor for a “pathogen associated molecular pattern”, formed by interaction of the conserved pathogen derived molecule (HMBPP) with BTN3A1-BTN2A1 [12]. Interestingly, isopentenyl pyrophosphate (IPP) an endogenous phospho-antigens, is a product of the mevalonate metabolic pathway in humans. This pathway is upregulated in cells undergoing metabolic stress during malignant transformation or inflammation, or by aminobisphosponate drugs. This leads to increased levels of IPP binding to BTN3A1 (albeit with far lower affinity than HMBPP) which induces Vg9d2 TCR+ cell activation to induce their secretion of inflammatory cytokines. [13].
The second major set of gd T cells , i.e. Vd1+ gd T cells, which typically exhibit tissue tropism culminating in epithelial surfaces, express a greater degree of TCR variability and clonal selection which is dependent upon exposure to pathogens, e.g. cytomegalovirus (CMV) and tuberculosis, suggesting more “adaptive feature” of this and similarly, of the Vd3+ gd and Vd5+ gd T subsets. These subsets recognize cell surface membrane molecules, some of which are induced during cellular stress, including annexin, ephrin A2, endothelial protein C receptor (EPCR), MHC or MHC like molecules (CD1d, a, b and c) as well as MHC class I polypeptide–related sequence A (MICA) and MHC class I-related gene protein (MR1), either in their native form or complexed to lipids [8,14]. In these instances, recognition is mediated primarily by the hypervariable CDR3 of Vd1 chains . Moreover, Vd1+ gd T cells can recognize shared haptens common to foreign and endogenous proteins [15]. These γδ T cell receptors (TCRs) may thus exhibit polyspecificity, recognizing multiple ligands of diverse molecular nature, and are poised to respond very early in an inflammatory reaction that may result in induction of such Vd1 ligands [15].
gd T cells in the periphery that are triggered by antigens binding to the TCR become activated, and exhibit a functional repertoire highly reminiscent of classical ab T cells, including cytotoxicity, cytokine production and even B cell helper functions [16]. In addition, tissue localized gd T cells help maintain and repair damaged tissues by secreting amphiregulin , keratinocyte growth factor, and insulin growth factor (IGF)-1 [17]. The vast majority of human gd T cells exhibit a T helper (Th)1 like cytokine producing repertoire, i.e. by production of IFNg, but a small yet important proportion may express a Th2 like profile [18]. By virtue of the ability to recognize stress induced cell surface molecules, gd T cells can interact with multiple immune and non immune cell types undergoing stress, and these interactions lead to activation of the appropriate functional programmes. For example, interactions with CD14+ monocytes with activated Vg9+ gd T cells may result in release of inflammatory cytokines including IL-1b and IFNg, by the monocytes, which enhances differentiation of macrophages to an M1 phenotype, whereas in adipose tissues gd T cells may drive their differentiation to an M2 phenotype [19,20].
Interestingly, in mice, a subset of gd T cells is pre-programmed in the thymus to emerge as “innate” IL-17 producing subset [21] . These γδ T17 cells, undergo “functional pre-commitment” in the thymus, express the canonical Th17 transcription factor retinoic acid receptor-related orphan receptor gamma (RORγ)t and are also characterized by expression of chemokine receptor 6 (CCR6), IL-23R, IL-1R, while lacking expression of CD27 [21]. Importantly, the thymic pre-programming obviates the necessity for TCR engagement for these cells to become activated to produce and secrete IL-17. Rather, they become directly activated by inflammasome induced cytokines – IL-1β, IL-18 and by IL-23, which directly induce production of IL-17A IL-17F, and sometimes of granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-22 . Thus, murine γδ T17 cells are poised for rapid reactivity to inflammasome activation occurring in reponse to pathogens, but also during inappropriate inflammasome activation such as occur in autoinflammatory conditions [22]. In humans, it is not clear whether an innate γδ T17 subset emerges from the thymus. However, it has been found that human Vg9d2+ gd T cells in the periphery can also be activated directly by inflammasome related products including IL-18 to produce cytokines [23]. Furthermore, nucleotide-binding oligomerization domain (NOD)-like receptors pyrin domain containing 3 (NLRP3) inflammasome has been directly linked to γδ T17 cell activation as demonstrated by the finding that tofacitinib, a Janus kinase (JAK) inhibitor, inhibits excessive NLRP3 inflammasome activation and concomitantly decreases γδT17 cell activation in a model of collagen induced arthritis [24]. In addition, endocytosed neutrophil extracellular traps (NET)-associated DNA components bind to an intracellular DNA sensor, absent in melanoma 2 (AIM2), which promotes AIM2 inflammasome activation and subsequent gasdermin D-mediated mitochondrial dysfunction, which suppresses the development of regulatory gd T cells [25] .
The nature of gd TCR reactivity, obviating MHC presentation, their functional programmes, tissue distribution and innate reactivity to stress induced molecules suggests they could participate not only in appropriate responses to inflammatory reactions e.g. to external pathogens, but could also be triggered during inappropriate auto-inflammation leading to autoinflammatory diseases, as depicted in Fig. 1. Despite the inherent link of gd T cells to inflammatory responses, the role of these cells have been studied in only a few of the diseases considered to exhibit a prominent autoinflammatory component. Herein, we summarized the currently available data in the scientific literature published in Pubmed, focusing on human diseases, in which the involvement of gd T cells was addressed. Our major goal was to obtain insights into the potential protective and/or pathogenic contribution of these cells in these diseases, which could suggest new investigative and therapeutic approaches.

gd T Cells in Monogenic Autoinflammatory Diseases

An increasing number of diseases characterized by monogenic mutations result in inappropriate inflammatory responses, but gd T cells have been evaluated in only a few, as described herein:
Familial Mediterranean Fever (FMF). This disease results from gain of function mutations in the MEFV gene on chromosome 16, which codes the pyrin molecule. Whereas in healthy individuals dephosphorylation of pyrin is not sufficient to provoke its activity, in FMF, dephosphorylation alone drives pyrin binding to the adaptor molecule apoptosis-associated speck-like protein containing a caspase recruitment domain (CARD) (ASC) and to caspase I, driving inflammasome activation and thus unprovoked inflammatory reactions. In this classical autoinflammatory disease, the percentage of PB gd T cells was not different from that of normal individuals, but the ability of the Vd2+ subset to secrete IFNg was diminished and there was a trend to increased number of CCR8+ Vδ2 T in FMF patients, suggesting increased homing capacity to the sites of inflammation in joints and serous surfaces [26,27].
HyperIgD syndrome (HIDS). This inflammatory syndrome, caused by mutations in the MVK gene, which codes for the enzyme mevalonate kinase, is characterized by attacks of chills, arthralgia, myalgia and abdominal pain, instigated by an increased secretion of IL-1β resulting from defective protein prenylation. Gd T cells in this syndrome have been found to be uniquely defective in their ability to produce TNFa and IFNg possibly due to defects in production of IPP, a downstream product of the mevalonate pathway that triggers activation of Vg9d2 gd T cells [28]
SAVI (STING-associated vasculopathy with onset in infancy ) is a compound autoimmune and autoinflammatory disease caused by heterozygous gain of function mutations of stimulator of interferon genes (STING) [29]. Although no studies of γδ T cells in SAVI have been reported, the characteristic T lymphocytopenia selectively affected the αβ T cell population but not γδ T cells in a murine model of this disease, suggesting their possible involvement in some of the inflammatory manifestations in humans as well [29].
Haploinsufficiency of A20 is caused by either a heterozygous tumor necrosis factor, alpha-induced protein 3 (TNFAIP3) pathogenic variant (~95% of affected individuals) or a heterozygous deletion of 6q23 including TNFAIP3. Patients exhibit febrile episodes, oral or genital ulcers, abdominal pain and arthritis, thus resembling BD. While no studies of gd T cells in humans with this disease have been reported, a murine model of Tnfaip3LysM-KO mice revealed a reduction of gd T cells in 18 week old mice compared to normal mice, and spontaneous accumulation of pulmonary Th1, Th17 and γδ-17 T cells in Tnfaip3LysM-KO Il17raKO mice [30].
Deficiency of adenosine deaminase type 2 (ADA2) (DADA2) is a rare inborn error of immunity caused by deleterious biallelic mutations in ADA2 causing a rare inborn error of immunity with recurrent fevers and vasculitis (ranging from livedo racemosa to polyarteritis nodosa and lacunar stroke) , immunodeficiency and cytopenia, either due to autoimmunity or bone marrow (BM) failure and hematological malignancy. In this disease, the proportions of γδ T cells were similar in healthy donors, heterozygous carriers and DADA2 patients but DADA2 patients had significantly fewer Vδ2+ cells (as well as other non conventional T cell subsets) than healthy donors [31].
VEXAS is caused by a reduction of the cytoplasmic UBA1 isoform by somatic UBA1 mutations, which decreases the efficiency of endoplasmic reticulum (ER) associated protein degradation. In this disease, characterized by recurrent fever, relapsing polychondritis, vasculitis, pneumonitis, orbital inflammatory syndrome, and Sweet syndrome, gd T cells exhibited elevated IFNa and IFNg gene module scores relative to healthy individuals, revealing their participation in the inflammatory process [32].
The pertinent features relating gd T cell perturbations in monogenic autoinflammatory diseases are summarized in Table 1.
Table 1. γδ T cells in monogenic autoinflammatory diseases. Summary of monogenic autoinflammatory disorders, their causative genes and dominant inflammatory pathways, and the principal quantitative or functional alterations described in γδ T-cell subsets, highlighting disease-specific insights into γδ T-cell involvement in autoinflammatory pathogenesis.

gd T Cells in Multifactorial/polygenic Autoinflammatory Disease

  • Diseases of Inappropriate autoinflammatory responses to well defined endogenous triggers.
Gout. Gout is an autoinflammatory disease induced by inflammasome activation driven by monosodium urate (MSU) crystals resulting in release of IL-1b and a downstream inflammatory response involving chiefly neutrophils in joints [33,34]. The NLRP3 inflammasome is a critical component in MSU induced inflammation Liu et al showed that serum IL-17 levels are significantly elevated in the PB early in the onset of symptoms of gout, and decrease as symptoms diminish. IL-17 expression correlated with serum levels of IL-1β . Flow cytometry analysis indicated that γδ T cells in the PB were the major source of IL-17 production during the early onset of acute gouty arthritis, when approximately 2% of the gd T cells produced IL-17 reducing to close to 0% when the attack abated [35]. By contrast the percentages of IFN-γ-producing Vδ2 T cells were lower than in normal individuals [27]. Interestingly moreover, an integrative bioinformatics analysis of the immune cell composition in the joints afflicted by gout revealed significant upregulation of M2 macrophages, activated mast cells, activated NK cells, and γδ T cells [36].An increase of γδ T cells in the joints was likewise reported in a Cibersort analysis of gouty arthritis [37]. Finally, a study of gene expression profiles of primary gout and atherosclerosis patients, revealed that differentially expressed genes (DEG) relative to normal, were significantly upregulated in activated CD4+ T cells, gd T cells, T follicular helper cell, CD56dim natural killer cells, and eosinophils, suggesting that gd T cells in gout express a unique gene expression profile relative to healthy individuals [38]. In summary, the data strongly reveal involvement of gd T cells in gout, both in the PB and in the joint space, which is characterized by increased IL-17 and reduced IFNg secretion by these cells.
Atherosclerosis: Activation of NLRP3 inflammasomes by cholesterol crystals and oxidized low density lipoproteins play a critical role in atherogenesis [39]. Although there was no prognostic association between the number of γδ T cells in PB in healthy individuals and subsequent occurrence of acute coronary events, an inflammatory response is triggered by the NLRP3 inflammasome in foam cells in atherosclerotic plaques, contributing to disease progression and plaque instability [40]. On the other hand, the frequencies and absolute numbers of total γδ T cells and Vδ2+ γδ T cells were found to be significantly decreased in patients with coronary artery disease (CAD) when compared to healthy individuals and the proportion of Vδ1+ T cells was much lower in the patients. However there was a positive correlation between serum low density lipoprotein (LDL) -C levels and frequencies of CD3+ γδ T cells, CD69+Vδ2+T cells, natural killer group 2D (NKG2D)+Vδ2+ γδ T cells, and NKp46+Vδ2+T cells [41]. Furthermore, gd T cells in the cardiac tissue during acute myocardial infarction were also depleted relative to normal tissues [42].Using CIBERSORT and ESTIMATE algorithms, the association between higher LGALS3BP (Galectin-3-binding protein), a glycoprotein which is implicated in inflammation, fibrosis, and cell-cell communication, and upregulated in response to cardiovascular stressors associated with adverse cardiac remodeling and immune cell infiltration, was studied. A positive correlation of LGALS3BP with activated dendritic cells, NK cells, memory CD4 T cells, naïve CD4 T cells, CD8 T cells, follicular helper T cells and gd T cells in atherosclerotic plaques was revealed, linking gd T cells to adverse atherosclerosis outcomes [43].Together the data suggest that PB Vδ2+ T cells may become activated in the presence of LDL driving their entrance into atherosclerotic plaques, resulting in peripheral depletion. The detrimental contribution of gd T cells in the context of cardiac atherosclerotic disease is compounded by the finding that higher proportions of γδ T cells in PB were associated with lower absolute (worse) left ventricular global circumferential strain per 1 SD higher proportion of γδ T cells in a study of older adults [44]. Moreover, in a study to evaluate the link of rheumatoid arthritis (RA) to atherosclerosis, two hub-shared genes, CD52 and TNFRSF17 genes were identified. Significant correlations between gd T cells and TNFRSF17 - also known as B-cell maturation antigen (BCMA)- in the infiltrate of immune cells suggest pathogenic interactions of gd T cells with B cells in atherosclerotic plaques and in RA [45]. Indeed, a separate study confirms increased gd T cells in atherosclerotic plaques, residing along with M0 macrophages, memory B cells, activated mast cells, and CD4 native T cells and in correlation with increased expression of collagen, type I, alpha 1 (COL1A1) [46]. Atheromatous plaque samples with a high pyroptosis score cluster, as a consequence of inflammasome activation, had higher proportions of gd T cells, M2 macrophages, myeloid dendritic cells (DCs), and cytotoxic lymphocytes (CTLs), but lower proportions of endothelial cells (ECs) [47]. NOD-like receptor signaling pathway and NF-kappa B signaling pathways were highly enriched in the pyroptosis score high cluster, suggesting a contribution of gd T cells activated by pyroptotic products in atherosclerotic vessels [47]. Further confirmation of the role of gd T cells in atherosclerotic plaques was obtained in an analysis of differentially expressed genes (DEG) in atherosclerotic plaques, and correlation of gd T cells with expression of CD52, a marker present on foam cells [48,49] . Atheromatous plaques in which immune cells were more highly expressed cluster had higher proportions of M0 macrophages and gd T cells but lower proportions of plasma cells and monocytes (p < 0.05). IL18 and other markers were commonly related to these immune cells suggesting a role for IL-18 in activation of plaque gd T cells [50]. Finally, although in mice, it IL-23 receptor R+ γδ T cells are predominantly found in the aortic root mice where they promote early atherosclerotic lesion formation, plaque necrosis, and inflammation, a study of human atherosclerotic plaques showed that IL-23 signaling activity was negatively associated with gd T cells [51,52]. IL-23 signalling may thus be instrumental in inducing elevated levels of ab and gd T cells IL-17A(+) T cells in the aortas of 21-week-old Apoe(-/-) mice fed a Western diet for 15 weeks, but non in humans [53]. Taken together, these studies suggest a model wherein gd T cells recruited from the PB accumulate in atherosclerotic plaques in response to LDL-C activated inflammasomes in myeloid derived foam cells, where they could contribute to local inflammation and plaque instability.
Parkinsons disease (PD). In this common neurodegenerative disease of motor function, over-activation of NLRP3 inflammasome in microglia is triggered by a synuclein which accumulates in PD and indirectly leads to the loss of nigrostriatal dopaminergic neurons [54]. A highly unusual CD4+ gd T cell population secreting IL-17, but not IFNg, was detected to be significantly increased in the PB of PD patients relative to healthy controls [55] . However, an analysis of the proportions of 22 immune cell types in PB using the CIBERSORT method as well as by flow cytometry revealed that compared with the immune cell proportions in blood samples of healthy control subjects, naïve CD4 T cells and gd T cells were significantly decreased in PD [56,57]. On the other hand, PB gd T cells in PD patients were higher than in other neurological diseases, and the gd T cells in the cerebrospinal fluid more frequently expressed CD25, suggesting an activated state [58] . Thus, the current limited data suggest activation of PB gd T cells to secrete IL-17, and that gd T cells in PD may be recruited to the central nervous system and become activated, perhaps by inflammatory products released by a synuclein induced activation of inflammasomes.
Alzheimers disease (AD). In AD, microglial exposure to pathological amyloid β (Aβ42) and tau peptide aggregates results in an NLRP3 inflammasome-activated pro-inflammatory response [59]. AD patients showed notably elevated proportions of gd T cells and activated CD4 memory T cells in afflicted brain tissue in comparison to healthy individuals, but not in PB, where they were, however, elevated relative to patients with mild cognitive impairment [60,61,62,63,64,65] . The gd T cells in brain exhibited reduced T cell receptor gamma variable (TRGV) 9 clonotypes but were enriched in TRGV2, 4 and 8 clonotypes which suggests that interactions with BTNL8 expressed in brain may play a role in the activity of gd T cells in AD [66]. AD-associated TRG profiles were found in both the PB and brain and some groups of clonotypes were more specific for the brain or blood in patients with AD compared to those in controls [67] .Recently, it was reported that higher total cognitive score correlated with lower expression of genes related to cytotoxicity, antigen presentation, and antimicrobial defense in PB gd T cells in AD [68,69]. Interestingly, in the murine 3xTg-AD model, an accumulation of IL-17-producing cells, mostly γδ T cells, in the brain and the meninges of female, but not male mice, concomitant with the onset of cognitive decline, suggests early involvement of gd T cells in the pathogenesis of AD [70].
2.
Diseases of Inappropriate autoinflammatory responses to poorly defined endogenous triggers.
Behcet`s disease (BD). Although the underlying causes of this systemic chronic inflammatory disease are complex, BD, a systemic vasculitis with protean clinical manifestations bears hallmarks of inappropriate inflammatory responses as well as autoimmunity [71]. Triggers of the autoinflammatory response may include bacteria (streptococcus sanguis), herpes simplex, heat shock proteins, environmental cues, and gut dysbiosis [71]. Due to their innate responsiveness to bacterial phosphoantigens, pathogen related haptens, and stress molecules gd T cells appear to be well positioned to respond to these putative triggers of inappropriate inflammation [72].In fact, gd T cell response to heat shock proteins was proposed as a useful diagnostic criterion for BD [73] . Furthermore, gd T cells from BD patients responded to a greater degree to a supernatant of bacterial cultures derived from the oral ulcers of a BD patient [26]. Likewise an augmented response to streptococcus sanguis is a specific property of BD CD8+ gd T cells [74]. In active disease, gd T cells secreted IFNg but not IL-17a, as opposed to CD4+ T cells which secreted both cytokines but could be triggered to secrete higher levels of both cytokines than normal under IL-17 inducing conditions [75,76]. Other studies suggest that PB gd T cells in both BD as well as in patients with recurrent aphthous ulcers are increased in the PB, express more CD69 and CD29 than in healthy controls, and secrete both IFNg and TNFa [77]. In addition, the Vd1+ subset among CD8+ gd T cells are increased in BD and secrete IFNg and TNFa [78]. There are conflicting reports with regard to the degree of expansion of gd T cells in the PB of patients, most consistently indicating expansion during active disease [79,80,81]. At a functional level, it has been found that BD Vg9Vd2+ gd T cells secrete higher levels of granzyme A than normal [82]. Moreover, these cells also expanded fivefold more in patients with active disease than in those with inactive disease or in control individuals in response to the phosphoantigen dimethylallyl pyrophosphate suggesting inappropriate response to phospho-antigens [83]. One of the major organs afflicted in BD is the eye. High numbers of gd T cells, predominantly expressiong Vg9Vd2 TCR , were detected in the intraocular fluid and responded to phospho-antigens by secreting IFNg and upregulating CD69 [84].Likewise, gd T-cells were numerous and observed in all recurrent aphthous lesions of BD patients especially within the epithelium, inflammatory infiltrates and at perivascular locations [85]. Taken together the data indicate an active pathogenic participation of gd T cells, of both major subsets – Vg9d2 and Vd1+ - in BD both in the circulating compartment as well as in afflicted organs, by secreting pro inflammatory cytokines and cytotoxic mediators
Systemic onset juvenile idiopathic arthritis (Still`s disease).Both the percentage and absolute number of gd T cells increased in active adult Still’s disease [86] . IL-17A was prevalent in sera from patients with Still`s disease, and ex vivo and in vitro experiments revealed γδ T cells overexpressing this cytokine. This was not seen with CD4+ T cells, which expressed strikingly low levels of IFNγ. Therapeutic IL-1 blockade was associated with partial normalization of both cytokine expression phenotypes. Furthermore, culturing healthy donor γδ T cells in serum from systemic JIA patients or in medium containing IL-1β, IL-18, and S100A12 induced IL-17 overexpression at levels similar to those observed in the patients’ cells [87]. These data suggest a central role for innate IL-1β and IL-18 activated IL-17 producing gd T cells during active Still`s disease.
Multisystem inflammatory syndrome associated with SARS-CoV-2 infection (MIS-C). MIS-C comprises multiorgan dysfunction and systemic inflammation developing in children infected with SARS-CoV-2 [88]. High levels of IL-1β, IL-6, IL-8, IL-10, IL-17, IFNγ and differential T and B cell subset lymphopenia were found in the PB during acute disease. High human leukocyte antigen (HLA)-DR expression on γδ and CD4+CCR7+ T cells were also found in the acute phase, but normalized at convalescence, suggesting that these immune cell populations were activated and played a role in disease pathogenesis [88].On the other hand, the number of gd T cells along with other T cell subsets including mucosal-associated invariant T cells (MAIT) and natural killer T (NKT) cells is reduced, in particular during severe disease [89]. Interestingly 2.2% of MIS-C patients harboured predicted-deleterious variants in BTNL8, which encodes a ligand for Vg4Vd1+ T cells in the gut, and which were not found in controls. Most of these variants were in the B30.2 domain of BTNL8 implicated in sensing epithelial cell status, and the ability of the encoded ligand to activate Vg4Vd1+ T cells was impaired. These data suggest a role for defects of Vg4Vd1+ T cells in the gut in the development of MIS-C associated enteropathy [90].
Kawasaki`s disease (KD). KD or muco-cutaneous lymph node syndrome, is a form of auto-inflammatory vasculitis of medium sized arteries including coronary arteries, manifesting with fever cervical lymphadenopathy and skin rash. CIBERSORTx immune cell infiltration analysis revealed that gd T cells, monocytes, M0 macrophage, activated dendritic cells, activated mast cells and neutrophils were all elevated in the arterial wall immune infiltrate in KD compared to healthy controls. In patients with coronary artery lesions, there was systemic upregulation of TNFSF13B, C-X-C chemokine ligand 16 (CXCL16), TNFSF10, and interleukin 1 receptor antagonist (IL1RN), mainly produced by monocytes [91]. On the other hand in the PB, in general, patients with KD had an increasing trend in B cells and monocytes and a reducing trend in CD4+ T, CD8+ T, MAIT, NK, and γδ T cells compared with controls [92]. A different study showed, however, an increase of gd T cells in the PB of patients [93]. These results suggest active systemic and local involvement of gd T cells at sites of inflammation in KD, which may be instigated by the cytokine storm characterizing this disease.
A summary of the pertinent features of γδ T cells in the multifactorial/polygenic autoinflammatory diseases is displayed in Table 2.
Table 2. γδ T cells in multifactorial / polygenic autoinflammatory diseases. A summary of multifactorial autoinflammatory conditions, their principal triggers and pathogenic pathways, and the characteristic γδ T-cell alterations observed in blood and tissues, highlighting shared and disease-specific γδ T-cell signatures across crystal-, metabolic-, infection-, and neuroinflammation-driven disorders.

Discussion

Autoinflammatory diseases exemplify the pathological consequences of dysregulated innate immune activation, most commonly driven by aberrant inflammasome signaling and excessive production of IL-1 family cytokines [1,2,3,4]. While neutrophils and macrophages are central executors of these responses, γδ T cells appear to function as critical intermediaries that translate innate immune activation into sustained cellular and cytokine-driven inflammation.
A defining feature of γδ T cells is their capacity to respond rapidly to stress signals without the need for classical antigen processing or MHC-restricted presentation [8,10]. This property allows them to sense both exogenous danger signals, such as pathogen-derived phosphoantigens, and endogenous cues, including cell surface molecules and intracellular phospho-antigens generated during metabolic stress, tissue injury, e.g resulting from crystal deposition [10,11,12,13]. Specific examples include upregulation of MICA molecule by inflammation which could affect functional outcomes of gd T cells via interactions with NKG2D and down regulation of EPCR during inflammation, decreasing interactions of EPCR reactive gd T cell clones [94,95].
Evidence from monogenic autoinflammatory diseases suggests that γδ T cell dysfunction is not uniform but instead reflects disease-specific alterations in signaling pathways. In FMF, γδ T cell frequencies are preserved, IL-17 is increased, yet Vδ2⁺ cells display impaired IFN-γ production and altered chemokine receptor expression, suggesting defective effector function and enhanced tissue homing [25,26]. In hyper-IgD syndrome, γδ T cells exhibit reduced TNFα and IFNγ secretion, likely reflecting impaired production of endogenous phosphoantigens downstream of the mevalonate pathway [27]. Murine models of interferonopathies and NF-κB dysregulation further implicate γδ T cells—particularly IL-17–producing subsets—in shaping inflammatory phenotypes [28,29]. In VEXAS on the other hand IFNg profiles increase, demonstrating adaptation of gd T cells to the immune environment specifically generated in each of the genetically distince monogenic diseases, and reflecting the plasticity of the gd T cell functional repertoirs [32].
In the multifactorial autoinflammatory diseases in which defined endogenous triggers have been identified, the contribution of γδ T cells is also apparent, having been studied in more detail. In gout, γδ T cells are a major early source of IL-17 in PB, with cytokine production tightly correlating with IL-1β levels and disease activity [30,31]. Transcriptomic and immune deconvolution analyses further demonstrate enrichment of γδ T cells within inflamed joints and altered γδ T cell gene expression profiles, supporting a direct role in disease pathogenesis [32,33,34]. Together, these findings place γδ T cells downstream of NLRP3 inflammasome activation and upstream of neutrophil-dominated joint inflammation.
A similar paradigm emerges in atherosclerosis, where cholesterol crystals and oxidized LDL activate NLRP3 inflammasomes within foam cells [35,36]. Although circulating γδ T cells—particularly Vδ2⁺ cells—are reduced in CAD, multiple studies demonstrate their accumulation within atherosclerotic plaques, where they associate with macrophages, dendritic cells, pyroptotic signaling, and markers of plaque instability [37,38,39,40,41,42,43,44,45,46]. Correlations between γδ T cell abundance, IL-18 signaling, and adverse cardiac remodeling further support a pathogenic role in vascular inflammation [40,43,46]. Differences between murine and human studies regarding IL-23 signaling and γδ T17 cell expansion may be attributed to the well known unique species-specific nature of gd T cells [47–49[96].
The involvement of γδ T cells in neurodegenerative diseases with an autoinflammatory component extends the concept that autoinflammation induced T cells, in addition to those induced by classical immune-mediated mechanisms, may play a role in central nervous system disease . In PD, α-synuclein–induced NLRP3 inflammasome activation in microglia is accompanied by altered γδ T cell frequencies and the emergence of IL-17–producing γδ T cell subsets, both in PB and cerebrospinal fluid [50,51,52,53,54]. In AD, γδ T cells accumulate within affected brain regions and display distinct TCR clonotypes, suggesting ligand-driven selection within the inflamed central nervous system, linking innate and antigen driven mechanisms of involvement in this disease [55,56,57,58,59,60,61,62,63]. Associations between γδ T cell gene expression signatures and cognitive performance further implicate these cells in disease progression [64,65,66].
Diseases characterized by poorly defined endogenous triggers, including BD, Still’s disease, Kawasaki disease, and MIS-C, provide additional insight into γδ T cell biology in cytokine-rich inflammatory environments. In BD, γδ T cells respond vigorously to microbial products, heat shock proteins, and phosphoantigens, expand during active disease, and secrete pro-inflammatory cytokines and cytotoxic mediators within affected tissues [67,68,69,70,71,72,73,74,75,76,77,78,79,80,81]. In Still’s disease, IL-1β- and IL-18–driven activation of IL-17–producing γδ T cells appears central to systemic inflammation and is partially reversed by IL-1 blockade [82,83]. In MIS-C and Kawasaki disease, immune profiling reveals activation and tissue infiltration of γδ T cells in the context of cytokine storms and vascular inflammation, implicating them in disease pathogenesis despite peripheral lymphopenia [84,85,86,87,88,89]. Moreover, in diseases where autoinflammation as well as autoimmunity have been implicated, such as BD, gd T cells activated during the inflammatory phase could serve as instigators and regulators of the autoimmune component of the disease by virtue of their ability to present antigens to ab T cells, activate autoreactive B cells or act as regulatory T cells [97,98,99,100].
Despite growing evidence linking γδ T cells to autoinflammatory pathology, important gaps remain. γδ T cells have been studied in only a small proportion of autoinflammatory diseases . Moreover, human γδ T cell subsets exhibit marked heterogeneity, and most available data are cross-sectional and derived from PB rather than inflamed tissues. Longitudinal studies, spatially resolved analyses, and functional perturbation experiments in each disease individually will be essential to distinguish precise pathogenic and regulatory roles of gd T cells in these instances.
From a therapeutic perspective, γδ T cells represent both a challenge and an opportunity. Indirect modulation through inflammasome inhibition, IL-1/IL-18 blockade, or metabolic pathway targeting already shows promise [23,83]. The contribution of IL-17 produced by gd T cells may explain in part the therapeutic efficacy of anti IL-17 therapy in gout [101]. The contribution of gd T cells to TNFa production may be partly responsible for the efficacy of anti TNFa treatmen in BD [102]. A more refined understanding of subset-specific γδ T cell functions may ultimately enable targeted interventions that suppress pathogenic inflammation while preserving tissue-protective immunity.
In summary, γδ T cells emerge as pivotal sensors and amplifiers of inappropriate innate immune activation across a wide range of autoinflammatory diseases. Their ability to integrate inflammasome-derived signals with tissue-specific stress responses positions them at the crossroads of innate and adaptive immunity, with significant implications for disease classification, pathogenesis, and therapy.

Funding

No funding supported this submission.

References

  1. Parentelli, AS; Lopes, AA; Rieux-Laucat, F; Hermine, O. Systemic auto-inflammatory diseases, auto-immune diseases and immune deficiencies: From independent to overlapped diseases approach. Autoimmun Rev. 2025, 24(11), 103901. [Google Scholar] [CrossRef] [PubMed]
  2. Kozu, KT; Nascimento, R; Aires, PP; Cordeiro, RA; Moura, TCL; Sztajnbok, FR; et al. Inflammatory turmoil within: an exploration of autoinflammatory disease genetic underpinnings, clinical presentations, and therapeutic approaches. Adv Rheumatol. 2024, 64(1), 62. [Google Scholar] [CrossRef] [PubMed]
  3. An, J; Marwaha, A; Laxer, RM. Autoinflammatory Diseases: A Review. J Rheumatol. 2024, 51(9), 848–61. [Google Scholar] [CrossRef]
  4. Klotgen, HW; Beltraminelli, H; Yawalkar, N; van Gijn, ME; Holzinger, D; Borradori, L. The expanding spectrum of clinical phenotypes associated with PSTPIP1 mutations: from PAPA to PAMI syndrome and beyond. Br J Dermatol 2018, 178(4), 982–3. [Google Scholar] [CrossRef] [PubMed]
  5. Bank, I; DePinho, RA; Brenner, MB; Cassimeris, J; Alt, FW; Chess, L. A functional T3 molecule associated with a novel heterodimer on the surface of immature human thymocytes. Nature 1986, 322(6075), 179–81. [Google Scholar] [CrossRef]
  6. Brenner, MB; McLean, J; Dialynas, DP; Strominger, JL; Smith, JA; Owen, FL; et al. Identification of a putative second T-cell receptor. Nature 1986, 322(6075), 145–9. [Google Scholar] [CrossRef]
  7. Hayday, AC. [gamma][delta] cells: a right time and a right place for a conserved third way of protection. Annu Rev Immunol. 2000, 18, 975–1026. [Google Scholar] [CrossRef]
  8. Sok, CL; Rossjohn, J; Gully, BS. The Evolving Portrait of gammadelta TCR Recognition Determinants. J Immunol. 2024, 213(5), 543–52. [Google Scholar] [CrossRef]
  9. Hu, Y; Hu, Q; Li, Y; Lu, L; Xiang, Z; Yin, Z; et al. gammadelta T cells: origin and fate, subsets, diseases and immunotherapy. Signal Transduct Target Ther. 2023, 8(1), 434. [Google Scholar] [CrossRef]
  10. Sanchez Sanchez, G; Papadopoulou, M; Azouz, A; Tafesse, Y; Mishra, A; Chan, JKY; et al. Identification of distinct functional thymic programming of fetal and pediatric human gammadelta thymocytes via single-cell analysis. Nat Commun. 2022, 13(1), 5842. [Google Scholar] [CrossRef]
  11. Herrmann, T; Karunakaran, MM. Butyrophilins: gammadelta T Cell Receptor Ligands, Immunomodulators and More. Front Immunol. 2022, 13, 876493. [Google Scholar] [CrossRef]
  12. Zhu, Y; Gao, W; Zheng, J; Bai, Y; Tian, X; Huang, T; et al. Phosphoantigen-induced inside-out stabilization of butyrophilin receptor complexes drives dimerization-dependent gammadelta TCR activation. Immunity 2025, 58(7), 1646–59 e5. [Google Scholar] [CrossRef]
  13. Boutin, L; Scotet, E. Towards Deciphering the Hidden Mechanisms That Contribute to the Antigenic Activation Process of Human Vgamma9Vdelta2 T Cells. Front Immunol. 2018, 9, 828. [Google Scholar] [CrossRef]
  14. Willcox, BE; Willcox, CR. gammadelta TCR ligands: the quest to solve a 500-million-year-old mystery. Nat Immunol. 2019, 20(2), 121–8. [Google Scholar] [CrossRef] [PubMed]
  15. Guo, J; Chowdhury, RR; Mallajosyula, V; Xie, J; Dubey, M; Liu, Y; et al. gammadelta T cell antigen receptor polyspecificity enables T cell responses to a broad range of immune challenges. Proc Natl Acad Sci U S A 2024, 121(4), e2315592121. [Google Scholar] [CrossRef] [PubMed]
  16. Hayday, AC; Vantourout, P. The Innate Biologies of Adaptive Antigen Receptors. Annu Rev Immunol. 2020, 38, 487–510. [Google Scholar] [CrossRef]
  17. Ribot, JC; Lopes, N; Silva-Santos, B. gammadelta T cells in tissue physiology and surveillance. Nat Rev Immunol. 2021, 21(4), 221–32. [Google Scholar] [CrossRef] [PubMed]
  18. Hsu, UH; Chiang, BL. gammadelta T Cells and Allergic Diseases. Clin Rev Allergy Immunol. 2023, 65(2), 172–82. [Google Scholar] [CrossRef]
  19. Takimoto, R; Suzawa, T; Yamada, A; Sasa, K; Miyamoto, Y; Yoshimura, K; et al. Zoledronate promotes inflammatory cytokine expression in human CD14-positive monocytes among peripheral mononuclear cells in the presence of gammadelta T cells. Immunology 2021, 162(3), 306–13. [Google Scholar] [CrossRef]
  20. LaMarche, NM; Kohlgruber, AC; Brenner, MB. Innate T Cells Govern Adipose Tissue Biology. J Immunol. 2018, 201(7), 1827–34. [Google Scholar] [CrossRef]
  21. Ribot, JC; Silva-Santos, B. Differentiation and activation of gammadelta T Lymphocytes: Focus on CD27 and CD28 costimulatory receptors. Adv Exp Med Biol. 2013, 785, 95–105. [Google Scholar]
  22. Papotto, PH; Ribot, JC; Silva-Santos, B. IL-17(+) gammadelta T cells as kick-starters of inflammation. Nat Immunol. 2017, 18(6), 604–11. [Google Scholar] [CrossRef]
  23. Gombert, D; Simeonov, J; Klein, K; Agaugue, S; Scheffold, A; Kabelitz, D; et al. Butyrophilin 3A/2A1-independent activation of human Vgamma9Vdelta2 gammadelta T cells by bacteria. PNAS Nexus 2025, 4(11), pgaf358. [Google Scholar] [CrossRef]
  24. Yang, X; Zhan, N; Jin, Y; Ling, H; Xiao, C; Xie, Z; et al. Tofacitinib restores the balance of gammadeltaTreg/gammadeltaT17 cells in rheumatoid arthritis by inhibiting the NLRP3 inflammasome. Theranostics 2021, 11(3), 1446–57. [Google Scholar] [CrossRef]
  25. Zeng, Y; Lin, J; Xiao, Z; Li, Z; Zheng, G; Zhou, Y; et al. Neutrophil extracellular traps exacerbate inflammatory arthritis by inhibiting gammadelta Treg cell differentiation via the AIM2 inflammasome. Redox Biol. 2025, 87, 103881. [Google Scholar] [CrossRef]
  26. Bank, I; Duvdevani, M; Livneh, A. Expansion of gammadelta T-cells in Behcet’s disease: role of disease activity and microbial flora in oral ulcers. J Lab Clin Med. 2003, 141(1), 33–40. [Google Scholar] [CrossRef]
  27. Al, B; Bruno, M; Roring, RJ; Moorlag, S; Suen, TK; Kluck, V; et al. Peripheral T Cell Populations are Differentially Affected in Familial Mediterranean Fever, Chronic Granulomatous Disease, and Gout. J Clin Immunol. 2023, 43(8), 2033–48. [Google Scholar] [CrossRef]
  28. Suen, TK; Al, B; Ulas, T; Reusch, N; Bahrar, H; Bekkering, S; et al. Human gammadelta T Cell Function Is Impaired Upon Mevalonate Pathway Inhibition. Immunology 2025, 175(3), 300–22. [Google Scholar] [CrossRef] [PubMed]
  29. Siedel, H; Roers, A; Rosen-Wolff, A; Luksch, H. Type I interferon-independent T cell impairment in a Tmem173 N153S/WT mouse model of STING associated vasculopathy with onset in infancy (SAVI). Clin Immunol. 2020, 216, 108466. [Google Scholar] [CrossRef] [PubMed]
  30. Vroman, H; Das, T; Bergen, IM; van Hulst, JAC; Ahmadi, F; van Loo, G; et al. House dust mite-driven neutrophilic airway inflammation in mice with TNFAIP3-deficient myeloid cells is IL-17-independent. Clin Exp Allergy 2018, 48(12), 1705–14. [Google Scholar] [CrossRef] [PubMed]
  31. Yap, JY; Moens, L; Lin, MW; Kane, A; Kelleher, A; Toong, C; et al. Intrinsic Defects in B Cell Development and Differentiation, T Cell Exhaustion and Altered Unconventional T Cell Generation Characterize Human Adenosine Deaminase Type 2 Deficiency. J Clin Immunol. 2021, 41(8), 1915–35. [Google Scholar] [CrossRef]
  32. Mizumaki, H; Gao, S; Wu, Z; Gutierrez-Rodrigues, F; Bissa, M; Feng, X; et al. In depth transcriptomic profiling defines a landscape of dysfunctional immune responses in patients with VEXAS syndrome. Nat Commun. 2025, 16(1), 4690. [Google Scholar] [CrossRef]
  33. Martinon, F; Petrilli, V; Mayor, A; Tardivel, A; Tschopp, J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 2006, 440(7081), 237–41. [Google Scholar] [CrossRef]
  34. So, AK; Martinon, F. Inflammation in gout: mechanisms and therapeutic targets. Nat Rev Rheumatol. 2017, 13(11), 639–47. [Google Scholar] [CrossRef]
  35. Liu, Y; Zhao, Q; Yin, Y; McNutt, MA; Zhang, T; Cao, Y. Serum levels of IL-17 are elevated in patients with acute gouty arthritis. Biochem Biophys Res Commun. 2018, 497(3), 897–902. [Google Scholar] [CrossRef] [PubMed]
  36. Yuan, Y; Gao, Z; Chen, J; Liu, Y; Zhou, J. Integrative bioinformatics analysis and experimental validation reveals key genes and regulatory mechanisms in the development of gout. Front Genet. 2025, 16, 1598835. [Google Scholar] [CrossRef] [PubMed]
  37. Zhang, M; Lin, Z; Liu, W. The immune microenvironment related biomarker CCL18 for patients with gout by comprehensive analysis. Comput Biol Chem. 2025, 115, 108334. [Google Scholar] [CrossRef]
  38. Xiao, L; Lin, S; Zhan, F. Identification of hub genes and transcription factors in patients with primary gout complicated with atherosclerosis. Sci Rep. 2024, 14(1), 3992. [Google Scholar] [CrossRef] [PubMed]
  39. Duewell, P; Kono, H; Rayner, KJ; Sirois, CM; Vladimer, G; Bauernfeind, FG; et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 2010, 464(7293), 1357–61. [Google Scholar] [CrossRef]
  40. Olson, NC; Sitlani, CM; Doyle, MF; Huber, SA; Landay, AL; Tracy, RP; et al. Innate and adaptive immune cell subsets as risk factors for coronary heart disease in two population-based cohorts. Atherosclerosis 2020, 300, 47–53. [Google Scholar] [CrossRef]
  41. Li, Y; Jiang, S; Li, J; Yin, M; Yan, F; Chen, Y; et al. Phenotypic Changes of Peripheral gammadelta T Cell and Its Subsets in Patients With Coronary Artery Disease. Front Immunol. 2022, 13, 900334. [Google Scholar] [CrossRef]
  42. Zhao, E; Xie, H; Zhang, Y. Predicting Diagnostic Gene Biomarkers Associated With Immune Infiltration in Patients With Acute Myocardial Infarction. Front Cardiovasc Med. 2020, 7, 586871. [Google Scholar] [CrossRef]
  43. Zhao, S; Zhao, C; Wang, L; Cheng, B; Zheng, M; Wang, X. Elucidating the role of LGALS3BP in coronary atherosclerosis: integrating bioinformatics and machine learning for advanced insights. J Cardiothorac Surg. 2025, 20(1), 338. [Google Scholar] [CrossRef]
  44. Sinha, A; Rivera, AS; Doyle, MF; Sitlani, C; Fohner, A; Huber, SA; et al. Association of immune cell subsets with cardiac mechanics in the Multi-Ethnic Study of Atherosclerosis. JCI Insight 2021, 6(13). [Google Scholar] [CrossRef] [PubMed]
  45. Zhao, P; Yuan, K; Tang, Z; Li, Y; Yu, Y; Gao, W; et al. Investigation of hub-shared genes and regulatory mechanisms of rheumatoid arthritis and atherosclerosis. Clin Rheumatol. 2025, 44(6), 2241–56. [Google Scholar] [CrossRef] [PubMed]
  46. Yong, X; Kang, T; Li, M; Li, S; Yan, X; Li, J; et al. Identification of novel biomarkers for atherosclerosis using single-cell RNA sequencing and machine learning. Mamm Genome 2025, 36(1), 183–99. [Google Scholar] [CrossRef] [PubMed]
  47. Liu, JW; Zhang, ZH; Lv, XS; Xu, MY; Ni, B; He, B; et al. Identification of key pyroptosis-related genes and microimmune environment among peripheral arterial beds in atherosclerotic arteries. Sci Rep. 2024, 14(1), 233. [Google Scholar] [CrossRef]
  48. Zheng, Z; Yuan, D; Shen, C; Zhang, Z; Ye, J; Zhu, L. Identification of potential diagnostic biomarkers of atherosclerosis based on bioinformatics strategy. BMC Med Genomics 2023, 16(1), 100. [Google Scholar] [CrossRef]
  49. Yin, Y; Xie, Z; Chen, D; Guo, H; Han, M; Zhu, Z; et al. Integrated investigation of DNA methylation, gene expression and immune cell population revealed immune cell infiltration associated with atherosclerotic plaque formation. BMC Med Genomics 2022, 15(1), 108. [Google Scholar] [CrossRef]
  50. Shen, Y; Xu, LR; Tang, X; Lin, CP; Yan, D; Xue, S; et al. Identification of potential therapeutic targets for atherosclerosis by analysing the gene signature related to different immune cells and immune regulators in atheromatous plaques. BMC Med Genomics 2021, 14(1), 145. [Google Scholar] [CrossRef]
  51. Gil-Pulido, J; Amezaga, N; Jorgacevic, I; Manthey, HD; Rosch, M; Brand, T; et al. Interleukin-23 receptor expressing gammadelta T cells locally promote early atherosclerotic lesion formation and plaque necrosis in mice. Cardiovasc Res. 2022, 118(14), 2932–45. [Google Scholar] [CrossRef]
  52. Han, H; Du, R; Cheng, P; Zhang, J; Chen, Y; Li, G. Comprehensive Analysis of the Immune Infiltrates and Aberrant Pathways Activation in Atherosclerotic Plaque. Front Cardiovasc Med. 2020, 7, 602345. [Google Scholar] [CrossRef] [PubMed]
  53. Smith, E; Prasad, KM; Butcher, M; Dobrian, A; Kolls, JK; Ley, K; et al. Blockade of interleukin-17A results in reduced atherosclerosis in apolipoprotein E-deficient mice. Circulation 2010, 121(15), 1746–55. [Google Scholar] [CrossRef]
  54. Yu, J; Zhao, Z; Li, Y; Chen, J; Huang, N; Luo, Y. Role of NLRP3 in Parkinson’s disease: Specific activation especially in dopaminergic neurons. Heliyon 2024, 10(7), e28838. [Google Scholar] [CrossRef] [PubMed]
  55. Diener, C; Hart, M; Kehl, T; Becker-Dorison, A; Tanzer, T; Schub, D; et al. Time-resolved RNA signatures of CD4+ T cells in Parkinson’s disease. Cell Death Discov. 2023, 9(1), 18. [Google Scholar] [CrossRef] [PubMed]
  56. Huang, Y; Liu, H; Hu, J; Han, C; Zhong, Z; Luo, W; et al. Significant Difference of Immune Cell Fractions and Their Correlations With Differential Expression Genes in Parkinson’s Disease. Front Aging Neurosci. 2021, 13, 686066. [Google Scholar] [CrossRef]
  57. Zhou, C; Zhou, X; He, D; Li, Z; Xie, X; Ren, Y. Reduction of Peripheral Blood iNKT and gammadeltaT Cells in Patients With Parkinson’s Disease: An Observational Study. Front Immunol. 2020, 11, 1329. [Google Scholar] [CrossRef]
  58. Fiszer, U; Mix, E; Fredrikson, S; Kostulas, V; Olsson, T; Link, H. gamma delta+ T cells are increased in patients with Parkinson’s disease. J Neurol Sci. 1994, 121(1), 39–45. [Google Scholar] [CrossRef]
  59. Ravichandran, KA; Brosseron, F; McManus, RM; Ising, C; Gorgen, S; Schmidt, S; et al. Enhancing Tyro3 signalling ameliorates IL-1beta production through STAT1 in Alzheimer’s disease models. J Leukoc Biol. 2025. [Google Scholar] [CrossRef]
  60. Du, W; Yu, S; Liu, R; Kong, Q; Hao, X; Liu, Y. Precision Prediction of Alzheimer’s Disease: Integrating Mitochondrial Energy Metabolism and Immunological Insights. J Mol Neurosci. 2025, 75(1), 5. [Google Scholar] [CrossRef]
  61. Chen, G; Xi, E; Gu, X; Wang, H; Tang, Q. The study on cuproptosis in Alzheimer’s disease based on the cuproptosis key gene FDX1. Front Aging Neurosci. 2024, 16, 1480332. [Google Scholar] [CrossRef]
  62. Lin, H; Su, L; Mao, D; Yang, G; Huang, Q; Lan, Y; et al. Identification of altered immune cell types and molecular mechanisms in Alzheimer’s disease progression by single-cell RNA sequencing. Front Aging Neurosci. 2024, 16, 1477327. [Google Scholar] [CrossRef] [PubMed]
  63. Wang, Y; Shen, Z; Wu, H; Yu, Z; Wu, X; Zhou, L; et al. Identification of genes related to glucose metabolism and analysis of the immune characteristics in Alzheimer’s disease. Brain Res. 2023, 1819, 148545. [Google Scholar] [CrossRef]
  64. Zhuang, X; Zhang, G; Bao, M; Jiang, G; Wang, H; Li, S; et al. Development of a novel immune infiltration-related diagnostic model for Alzheimer’s disease using bioinformatic strategies. Front Immunol. 2023, 14, 1147501. [Google Scholar] [CrossRef]
  65. Shigemizu, D; Mori, T; Akiyama, S; Higaki, S; Watanabe, H; Sakurai, T; et al. Identification of potential blood biomarkers for early diagnosis of Alzheimer’s disease through RNA sequencing analysis. Alzheimers Res Ther. 2020, 12(1), 87. [Google Scholar] [CrossRef]
  66. Dart, RJ; Zlatareva, I; Vantourout, P; Theodoridis, E; Amar, A; Kannambath, S; et al. Conserved gammadelta T cell selection by BTNL proteins limits progression of human inflammatory bowel disease. Science 2023, 381(6663), eadh0301. [Google Scholar] [CrossRef] [PubMed]
  67. Aliseychik, M; Patrikeev, A; Gusev, F; Grigorenko, A; Andreeva, T; Biragyn, A; et al. Dissection of the Human T-Cell Receptor gamma Gene Repertoire in the Brain and Peripheral Blood Identifies Age- and Alzheimer’s Disease-Associated Clonotype Profiles. Front Immunol. 2020, 11, 12. [Google Scholar] [CrossRef]
  68. Dressman, D; Winford, ED; Vardarajan, BN; Yidenk, M; Talcoff, R; Mazen, J; et al. Basic Science and Pathogenesis. Alzheimers Dement. 2025, 21 Suppl 1(Suppl 1), e107352. [Google Scholar] [CrossRef]
  69. Kloske, CM; Mahinrad, S; Barnum, CJ; Batista, AF; Bradshaw, EM; Butts, B; et al. Advancements in Immunity and Dementia Research: Highlights from the 2023 AAIC Advancements: Immunity Conference. Alzheimers Dement. 2025, 21(1), e14291. [Google Scholar] [CrossRef]
  70. Brigas, HC; Ribeiro, M; Coelho, JE; Gomes, R; Gomez-Murcia, V; Carvalho, K; et al. IL-17 triggers the onset of cognitive and synaptic deficits in early stages of Alzheimer’s disease. Cell Rep. 2021, 36(9), 109574. [Google Scholar] [CrossRef]
  71. Emmi, G; Bettiol, A; Hatemi, G; Prisco, D. Behcet’s syndrome. Lancet 2024, 403(10431), 1093–108. [Google Scholar] [CrossRef]
  72. Hayday, AC. gammadelta T Cell Update: Adaptate Orchestrators of Immune Surveillance. J Immunol. 2019, 203(2), 311–20. [Google Scholar] [CrossRef] [PubMed]
  73. Hasan, A; Fortune, F; Wilson, A; Warr, K; Shinnick, T; Mizushima, Y; et al. Role of gamma delta T cells in pathogenesis and diagnosis of Behcet’s disease. Lancet 1996, 347(9004), 789–94. [Google Scholar] [CrossRef]
  74. Nishida, T; Hirayama, K; Nakamura, S; Ohno, S. Proliferative response of CD8+ gamma delta+ T cells to Streptococcus sanguis in patients with Behcet’s disease. Ocul Immunol Inflamm. 1998, 6(3), 139–44. [Google Scholar] [CrossRef] [PubMed]
  75. DIM, A; Emery, P. Rheumatoid arthritis: a review of the key clinical features and ongoing challenges of the disease. Panminerva Med. 2024, 66(4), 427–42. [Google Scholar]
  76. Deniz, R; Tulunay-Virlan, A; Ture Ozdemir, F; Unal, AU; Ozen, G; Alibaz-Oner, F; et al. Th17-Inducing Conditions Lead to in vitro Activation of Both Th17 and Th1 Responses in Behcet’s Disease. Immunol Invest. 2017, 46(5), 518–25. [Google Scholar] [CrossRef]
  77. Freysdottir, J; Lau, S; Fortune, F. Gammadelta T cells in Behcet’s disease (BD) and recurrent aphthous stomatitis (RAS). Clin Exp Immunol. 1999, 118(3), 451–7. [Google Scholar] [CrossRef]
  78. Clemente Ximenis, A; Crespi Bestard, C; Cambra Conejero, A; Pallares Ferreres, L; Juan Mas, A; Olea Vallejo, JL; et al. In vitro evaluation of gammadelta T cells regulatory function in Behcet’s disease patients and healthy controls. Hum Immunol. 2016, 77(1), 20–8. [Google Scholar] [CrossRef]
  79. Parlakgul, G; Guney, E; Erer, B; Kilicaslan, Z; Direskeneli, H; Gul, A; et al. Expression of regulatory receptors on gammadelta T cells and their cytokine production in Behcet’s disease. Arthritis Res Ther. 2013, 15(1), R15. [Google Scholar] [CrossRef]
  80. Yasuoka, H; Yamaguchi, Y; Mizuki, N; Nishida, T; Kawakami, Y; Kuwana, M. Preferential activation of circulating CD8+ and gammadelta T cells in patients with active Behcet’s disease and HLA-B51. Clin Exp Rheumatol. 2008, 26((4) Suppl 50, S59–63. [Google Scholar]
  81. Treusch, M; Vonthein, R; Baur, M; Gunaydin, I; Koch, S; Stubiger, N; et al. Influence of human recombinant interferon-alpha2a (rhIFN-alpha2a) on altered lymphocyte subpopulations and monocytes in Behcet’s disease. Rheumatology (Oxford) 2004, 43(10), 1275–82. [Google Scholar] [CrossRef]
  82. Accardo-Palumbo, A; Ferrante, A; Cadelo, M; Ciccia, F; Parrinello, G; Lipari, L; et al. The level of soluble Granzyme A is elevated in the plasma and in the Vgamma9/Vdelta2 T cell culture supernatants of patients with active Behcet’s disease. Clin Exp Rheumatol. 2004, 22((4) Suppl 34, S45–9. [Google Scholar]
  83. Triolo, G; Accardo-Palumbo, A; Dieli, F; Ciccia, F; Ferrante, A; Giardina, E; et al. Vgamma9/Vdelta2 T lymphocytes in Italian patients with Behcet’s disease: evidence for expansion, and tumour necrosis factor receptor II and interleukin-12 receptor beta1 expression in active disease. Arthritis Res Ther. 2003, 5(5), R262–8. [Google Scholar] [CrossRef]
  84. Verjans, GM; van Hagen, PM; van der Kooi, A; Osterhaus, AD; Baarsma, GS. Vgamma9Vdelta2 T cells recovered from eyes of patients with Behcet’s disease recognize non-peptide prenyl pyrophosphate antigens. J Neuroimmunol. 2002, 130(1-2), 46–54. [Google Scholar] [CrossRef] [PubMed]
  85. Natah, SS; Hayrinen-Immonen, R; Hietanen, J; Patinen, P; Malmstrom, M; Savilahti, E; et al. Increased density of lymphocytes bearing gamma/delta T-cell receptors in recurrent aphthous ulceration (RAU). Int J Oral Maxillofac Surg. 2000, 29(5), 375–80. [Google Scholar] [CrossRef]
  86. Hoshino, T; Ohta, A; Nakao, M; Ota, T; Inokuchi, T; Matsueda, S; et al. TCR gamma delta + T cells in peripheral blood of patients with adult Still’s disease. J Rheumatol. 1996, 23(1), 124–9. [Google Scholar] [PubMed]
  87. Kessel, C; Lippitz, K; Weinhage, T; Hinze, C; Wittkowski, H; Holzinger, D; et al. Proinflammatory Cytokine Environments Can Drive Interleukin-17 Overexpression by gamma/delta T Cells in Systemic Juvenile Idiopathic Arthritis. Arthritis Rheumatol. 2017, 69(7), 1480–94. [Google Scholar] [CrossRef]
  88. Carter, MJ; Fish, M; Jennings, A; Doores, KJ; Wellman, P; Seow, J; et al. Peripheral immunophenotypes in children with multisystem inflammatory syndrome associated with SARS-CoV-2 infection. Nat Med. 2020, 26(11), 1701–7. [Google Scholar] [CrossRef] [PubMed]
  89. Mukund, K; Nayak, P; Ashokkumar, C; Rao, S; Almeda, J; Betancourt-Garcia, MM; et al. Immune Response in Severe and Non-Severe Coronavirus Disease 2019 (COVID-19) Infection: A Mechanistic Landscape. Front Immunol. 2021, 12, 738073. [Google Scholar] [CrossRef]
  90. Bellos, E; Santillo, D; Vantourout, P; Jackson, HR; Duret, A; Hearn, H; et al. Heterozygous BTNL8 variants in individuals with multisystem inflammatory syndrome in children (MIS-C). J Exp Med. 2024, 221(12). [Google Scholar] [CrossRef]
  91. Xie, Y; Shi, H; Han, B. Bioinformatic analysis of underlying mechanisms of Kawasaki disease via Weighted Gene Correlation Network Analysis (WGCNA) and the Least Absolute Shrinkage and Selection Operator method (LASSO) regression model. BMC Pediatr. 2023, 23(1), 90. [Google Scholar] [CrossRef] [PubMed]
  92. Chen, Y; Yang, M; Zhang, M; Wang, H; Zheng, Y; Sun, R; et al. Single-Cell Transcriptome Reveals Potential Mechanisms for Coronary Artery Lesions in Kawasaki Disease. Arterioscler Thromb Vasc Biol. 2024, 44(4), 866–82. [Google Scholar] [CrossRef] [PubMed]
  93. Liu, D; Song, M; Jing, F; Liu, B; Yi, Q. Diagnostic Value of Immune-Related Genes in Kawasaki Disease. Front Genet. 2021, 12, 763496. [Google Scholar] [CrossRef]
  94. Kohga, K; Tatsumi, T; Tsunematsu, H; Aono, S; Shimizu, S; Kodama, T; et al. Interleukin-1beta enhances the production of soluble MICA in human hepatocellular carcinoma. Cancer Immunol Immunother. 2012, 61(9), 1425–32. [Google Scholar] [CrossRef] [PubMed]
  95. Kondreddy, V; Keshava, S; Esmon, CT; Pendurthi, UR; Rao, LVM. A critical role of endothelial cell protein C receptor in the intestinal homeostasis in experimental colitis. Sci Rep. 2020, 10(1), 20569. [Google Scholar] [CrossRef] [PubMed]
  96. Pinheiro, RGR; Silva-Santos, B. Reaching maturity: Thymic gammadelta T cell differentiation in mice and humans. Sci Immunol. 2025, 10(114), eadn2093. [Google Scholar] [CrossRef]
  97. Khoshbakht, S; Baskurt, D; Vural, A; Vural, S. Behcet’s Disease: A Comprehensive Review on the Role of HLA-B*51, Antigen Presentation, and Inflammatory Cascade. Int J Mol Sci. 2023, 24(22). [Google Scholar] [CrossRef]
  98. Brandes, M; Willimann, K; Moser, B. Professional antigen-presentation function by human gammadelta T Cells. Science 2005, 309(5732), 264–8. [Google Scholar] [CrossRef]
  99. Huang, Y; Getahun, A; Heiser, RA; Detanico, TO; Aviszus, K; Kirchenbaum, GA; et al. gammadelta T Cells Shape Preimmune Peripheral B Cell Populations. J Immunol. 2016, 196(1), 217–31. [Google Scholar] [CrossRef]
  100. Peters, C; Kabelitz, D; Wesch, D. Regulatory functions of gammadelta T cells. Cell Mol Life Sci. 2018, 75(12), 2125–35. [Google Scholar] [CrossRef]
  101. Raucci, F; Iqbal, AJ; Saviano, A; Minosi, P; Piccolo, M; Irace, C; et al. IL-17A neutralizing antibody regulates monosodium urate crystal-induced gouty inflammation. Pharmacol Res. 2019, 147, 104351. [Google Scholar] [CrossRef] [PubMed]
  102. Talarico, R; Italiano, N; Emmi, G; Piga, M; Cantarini, L; Mattioli, I; et al. Efficacy and safety of infliximab or adalimumab in severe mucocutaneous Behcet’s syndrome refractory to traditional immunosuppressants: a 6-month, multicentre, randomised controlled, prospective, parallel group, single-blind trial. Ann Rheum Dis 2024. [Google Scholar] [CrossRef] [PubMed]
Table 1. γδ T Cells in Monogenic Autoinflammatory diseases. 
Table 1. γδ T Cells in Monogenic Autoinflammatory diseases. 
Disease Gene Dominant Inflammatory Pathway Key γδ T Cell Insight Refs
Familial Mediterranean Fever (FMF) MEFV Pyrin inflammasome → IL-1β Preserved numbers but reduced IFN-γ production by Vδ2⁺ cells; increased CCR8⁺ subset suggests enhanced tissue homing [25,26]
Hyper-IgD Syndrome (HIDS) MVK Mevalonate pathway defect → IL-1β Impaired TNF-α and IFN-γ secretion due to defective Vγ9Vδ2 activation (↓ IPP) [27]
SAVI TMEM173 Constitutive STING → type I IFN Relative γδ T-cell preservation amid αβ lymphopenia suggests participation in IFN-driven inflammation [28]
HA20 TNFAIP3 NF-κB dysregulation Reduced number, but pathogenic γδ-17 accumulation in inflamed tissues (murine models) [29]
DADA2 ADA2 inborn error of immunity Vd2+ cells reduced [31]
VEXAS UBA1 Myeloid ubiquitin-stress inflammation elevated IFNa and IFNg gene module scores [32]
Table 2. γδ T Cells in Multifactorial / Polygenic Autoinflammatory Diseases. 
Table 2. γδ T Cells in Multifactorial / Polygenic Autoinflammatory Diseases. 
Disease Key Trigger / Pathway Dominant Autoinflammatory Mechanism γδ T Cell Signature (Key Findings) References
Gout Monosodium urate crystals; NLRP3 IL-1β–driven inflammasome activation with neutrophil-mediated joint inflammation Major early source of IL-17 in blood and joints; reduced IFN-γ production by Vδ2⁺ cells; [30,31,32,33,34]
Atherosclerosis Cholesterol crystals, oxLDL; NLRP3 Foam-cell inflammasome activation, pyroptosis, chronic plaque inflammation Decreased γδ T cells in blood ; accumulation in plaques; associated with IL-18 signaling, macrophages, and plaque instability. [35,36,37,38,39,40,41,42,43,44,45,46,47,48,49]
Parkinson’s disease α-Synuclein; NLRP3 Microglial inflammasome activation and neuroinflammation Activated IL-17–CD4+γδ T cells; variable blood levels; recruitment to CNS and activation [50,51,52,53,54]
Alzheimer’s disease Amyloid-β, tau; NLRP3 Chronic microglial inflammasome-driven neuroinflammation Enrichment in brain tissue; skewed TCR repertoire (↓TRGV9, ↑TRGV2/4/8); IL-17–producing γδ T cells in mouse model early in disease [55,56,57,58,59,60,61,62,63,64,65,66]
Behçet’s disease Microbial, stress and heat-shock antigens Innate-like immune activation with autoinflammatory and autoimmune features Expansion and activation of Vγ9Vδ2⁺ and Vδ1⁺ γδ T cells; secretion of IFN-γ, TNF-α, granzyme A; prominent tissue infiltration [67,68,69,70,71,72,73,74,75,76,77,78,79,80,81]
Systemic-onset JIA (Still’s disease) IL-1β, IL-18 Cytokine-driven innate autoinflammation Increased circulating γδ T cells with dominant IL-17A production; phenotype partially normalizes with IL-1 blockade [82,83]
MIS-C (SARS-CoV-2) Post-infectious immune dysregulation Systemic cytokine storm with lymphopenia Numerical reduction but strong activation (HLA-DR⁺); BTNL8 variants impair gut Vγ4Vδ1⁺ γδ T-cell responses [84,85,86]
Kawasaki disease Unknown (likely infection-triggered inflammation) Medium-vessel vasculitis with cytokine storm γδ T cells enriched in coronary artery infiltrates; peripheral blood findings suggesting redistribution to inflamed tissue [87,88,89]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.
Copyright: This open access article is published under a Creative Commons CC BY 4.0 license, which permit the free download, distribution, and reuse, provided that the author and preprint are cited in any reuse.
Prerpints.org logo

Preprints.org is a free preprint server supported by MDPI in Basel, Switzerland.

facebook logotwitter logolinkedin logo
bsky
MDPI Initiatives
Important Links
Subscribe

Disclaimer

Terms of Use

Privacy Policy

Privacy Settings

© 2026 MDPI (Basel, Switzerland) unless otherwise stated