TIM3 Mediates T Cell Exhaustion during Mycobacterium tuberculosis Infection

PLoS Pathog. 2016 Mar 11;12(3):e1005490. doi: 10.1371/journal.ppat.1005490. eCollection 2016 Mar.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation
  • Hepatitis A Virus Cellular Receptor 2
  • Humans
  • Immunity
  • Interleukin-10 / metabolism
  • Interleukin-2 / metabolism
  • Mice
  • Mycobacterium tuberculosis / immunology*
  • Receptors, Virus / genetics
  • Receptors, Virus / metabolism*
  • T-Lymphocytes / immunology*
  • Tuberculosis / immunology*

Substances

  • Havcr2 protein, mouse
  • Hepatitis A Virus Cellular Receptor 2
  • IL10 protein, mouse
  • Interleukin-2
  • Receptors, Virus
  • Interleukin-10