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T-cell exhaustion

An estimated one-fourth of the world’s population is latently infected with Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB). Within this group, only a small percentage develop active and contagious disease, and in both humans and mouse models, the mechanisms underlying this progression to symptomatic TB remain unclear. Many factors contribute to the efficacy of the immune system in eliminating pathogens, but literature demonstrates a requirement for CD4+ T-cells in order to mount a protective response against Mtb. Accordingly, one possible explanation for bacterial recrudescence and the progression of latent to active TB is CD4+ T-cell exhaustion. However, T-cell exhaustion has primarily been studied in the context of CD8+ T-cells in chronic viral infection and cancer models. As such, our lab uses mouse models of TB to study the CD4+ T-cell response in chronic Mtb infection to determine the phenotypic and transcriptional characteristics of CD4+ T-cell exhaustion and the mechanisms that mediate it.

We previously demonstrated that dysfunctional PD-1+ TIM-3+ double positive T-cells accumulate in the lungs of chronically infected C57Bl/6 mice, and these T-cells exhibit a transcriptional signature associated with T-cell exhaustion (Jayaraman et al., 2016). We are currently working to more rigorously characterize exhausted antigen-specific T-cells using C7 TCR transgenic mice with CD4+ T-cells specific to ESAT-61-15 (C7 T-cells) and NGS platforms. We also previously presented that susceptible C3HeB/FeJ mice succumbed to infection earlier and had a higher lung bacterial burden than TIM-3 KO mice on the same background. Furthermore, blockade of TIM-3 in C57Bl/6 mice results in a lower lung bacterial burden compared to isotype controls, suggesting that the inhibitory receptor, TIM-3, plays a role in mediating T-cell exhaustion during TB (Jayaraman et al., 2016). However, the mechanism through which TIM-3 promotes bacterial survival and mediates exhaustion remains an active question in the lab.

A newer arm of this project has stemmed from the discovery that TIM-3 also regulates innate immunity. Recent studies have found links between the mutations in TIM-3 that prevent its expression on the cell surface and increased IL-1b and inflammation, resulting in the human disease SPTCL. Currently, we hypothesize that TIM-3 negatively regulates inflammasome activation, and we predict that disruption of TIM-3:ligand interactions will disinhibit the inflammasome, lead to IL-1b and IL-18 secretion, and secondarily affect TNF and type I IFN production. As these cytokines all affect the outcome of TB and other infections, we expect that the TIM-3/inflammasome axis will regulate innate immunity to TB.