IL-10-Producing CD8⁺ T Cells Impair Immune Control During Chronic Mycobacterium tuberculosis Infection

Chronic Mycobacterium tuberculosis (M.tb) infection reflects failure of sterilizing immunity and persistent pulmonary bacterial burden. While CD4+ T cells and IFN-γ are central to protection, the role of CD8+ T cells in chronic disease remains unclear. This study examined whether CD8+ T cells contribute to immune dysregulation during chronic tuberculosis through IL-10 production. Susceptible CBA/J and resistant C57BL/6 mice were infected with a low-dose aerosol of M.tb Erdman and followed for 150 days. Lung bacterial burden, cytokine responses, and T-cell populations were assessed using high-purity CD8+ T-cell isolation (>97%), ELISA, ELISPOT, and in vivo CD8+ depletion. In susceptible CBA/J mice, chronic infection was associated with progressive pulmonary accumulation of CD8+ T cells, reduced CD4:CD8+ ratios, increased IL-10 levels, and impaired bacterial control. Antigen-experienced CD8+ T cells were a major source of IL-10, which correlated with reduced IFN-γ responses and higher bacterial burden. CD8+ depletion during chronic infection was associated with reduced bacterial burden and increased IFN-γ responses. Resistant C57BL/6 mice showed limited expansion of IL-10-associated CD8+ responses and better bacterial control. These findings support a model in which chronic M.tb infection is associated with expansion of IL-10-producing CD8+ T cells in susceptible hosts and altered immune control. CD8+ T-cell modulation during chronic disease is associated with changes in bacterial burden, suggesting a contributory role in disease outcome. These results highlight CD8+ T-cell functional polarization as a factor to consider in tuberculosis pathogenesis and vaccine design.