TIM3 Mediates T Cell Exhaustion during Mycobacterium tuberculosis Infection

PLoS Pathogens

Britni L. Stowell¹  Pushpa Jayaraman¹  Miye K. Jacques¹  Samuel M. Behar¹  Katherine M. Steblenko¹  Chen Zhu²  Asaf Madi²  Ana C. Anderson²  Vijay K. Kuchroo² 

[1] Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America;Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America

关键词: T cells;    Mycobacterium tuberculosis;    Cytotoxic T cells;    T cell receptors;    CD coreceptors;    Cytokines;    Tuberculosis;    Cell-mediated immunity;   

DOI  :  10.1371/journal.ppat.1005490

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY