期刊
PLOS PATHOGENS
卷 12, 期 3, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.ppat.1005490
关键词
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资金
- National Institutes of Health [R01 AI085669, AI098637, R01 NS045937, P01 AI073748]
- American Lung Association postdoctoral research training fellowship [RT-123085-N]
- Harvard University Center for AIDS Research (CFAR) Scholar Award
- NIH [P30 AI060354]
- NIAID
- NCI
- NICHD
- NHLBI
- NIDA
- NIMH
- NIA
- NCCAM
- FIC
- OAR
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.
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