TIM3 Mediates T Cell Exhaustion during Mycobacterium tuberculosis Infection.

Pushpa Jayaraman, Miye K Jacques, Chen Zhu, Katherine M Steblenko, Britni L Stowell, Asaf Madi, Ana C Anderson, Vijay K Kuchroo, Samuel M Behar

PLoS pathogens 2016 Mar

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While T cell immunity initially limits Mycobacterium tuberculosis infection, why T cell immunity fails to sterilize the infection and allows recrudescence is not clear. One hypothesis is that T cell exhaustion impairs immunity and is detrimental to the outcome of M. tuberculosis infection. Here we provide functional evidence for the development T cell exhaustion during chronic TB. Second, we evaluate the role of the inhibitory receptor T cell immunoglobulin and mucin domain-containing-3 (TIM3) during chronic M. tuberculosis infection. We find that TIM3 expressing T cells accumulate during chronic infection, co-express other inhibitory receptors including PD1, produce less IL-2 and TNF but more IL-10, and are functionally exhausted. Finally, we show that TIM3 blockade restores T cell function and improves bacterial control, particularly in chronically infected susceptible mice. These data show that T cell immunity is suboptimal during chronic M. tuberculosis infection due to T cell exhaustion. Moreover, in chronically infected mice, treatment with anti-TIM3 mAb is an effective therapeutic strategy against tuberculosis.

Citation

Pushpa Jayaraman, Miye K Jacques, Chen Zhu, Katherine M Steblenko, Britni L Stowell, Asaf Madi, Ana C Anderson, Vijay K Kuchroo, Samuel M Behar. TIM3 Mediates T Cell Exhaustion during Mycobacterium tuberculosis Infection. PLoS pathogens. 2016 Mar;12(3):e1005490