Abstract
The exact role of CD8+ T cells during Mycobacterium tuberculosis (Mtb) infection has been heavily debated, yet it is generally accepted that CD8+ T cells contribute to protection against Mtb. In this study, however, we show that the Mtb-susceptible CBA/J mouse strain accumulates large numbers of CD8+ T cells in the lung as infection progresses, and that these cells display a dysfunctional and immunosuppressive phenotype (PD-1+, Tim-3+, CD122+). CD8+ T cell expansions from the lungs of Mtb-infected CBA/J mice were also capable of secreting the immunosuppressive cytokine interleukin-10 (IL-10), although in vivo CD8+ T cell depletion did not significantly alter Mtb burden. Further analysis revealed that pulmonary CD8+ T cells from Mtb-infected CBA/J mice were clonally expanded, preferentially expressing T cell receptor (TcR) Vβ chain 8 (8.2, 8.3) or Vβ 14. Although Vβ8+ CD8+ T cells were responsible for the majority of IL-10 production, in vivo depletion of Vβ8+ did not significantly change the outcome of Mtb infection, which we hypothesize was a consequence of their dual IL-10/IFN-γ secreting profiles. Our data demonstrate that IL-10-secreting CD8+ T cells can arise during chronic Mtb infection, although the significance of this T cell population in tuberculosis pathogenesis remains unclear.
Highlights
The factors that are responsible for the reactivation of latent Mycobacterium tuberculosis (Mtb) infection are not well understood, but likely involve contributions from both the host and the pathogen
We have demonstrated that clonal expansions of CD8+ T cells from CBA/J mice accumulate in the lung over the course of Mtb infection
This accumulation did not yield an equivalent increase in IFN-c+CD8+ T cells and, upon further phenotypic examination, we discovered that highly activated CD8+ T cells from CBA/J mice expressed the T cell dysfunction markers programmed cell death-1 (PD-1) and T cell immunoglobulin and mucin protein-3 (Tim-3), as well as co-expression of PD-1 and CD122 suggesting possible immunosuppressive activity
Summary
The factors that are responsible for the reactivation of latent Mtb infection are not well understood, but likely involve contributions from both the host and the pathogen. To appreciate the role that the host immune system plays in Mtb reactivation, we used relatively resistant (C57BL/6) or susceptible (CBA/J) mice, whose susceptibility phenotype is most apparent during late stages of infection, to represent differences in the natural progression of TB between different human populations. CD8+ T cells are an important component of the protective immune response to Mtb, as defined by studies showing that mice deficient in CD8+ T cells had impaired control of Mtb infection [7,8,9,10]. Studies have reported that CD8+ T cells are most important during latent Mtb infection in mice, and that CD8+ T cell depletion early after infection had little effect on disease outcome [18]. Other studies suggest that CD8+ T cells are dispensable during Mtb infection [19,20,21]
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