Jayaraman, PushpaJacques, Miye K.Zhu, ChenSteblenko, Katherine M.Stowell, Britni L.Madi, AsafAnderson, AnaKuchroo, VijayBehar, Samuel M.2016-04-012016Jayaraman, Pushpa, Miye K. Jacques, Chen Zhu, Katherine M. Steblenko, Britni L. Stowell, Asaf Madi, Ana C. Anderson, Vijay K. Kuchroo, and Samuel M. Behar. 2016. “TIM3 Mediates T Cell Exhaustion during Mycobacterium tuberculosis Infection.” PLoS Pathogens 12 (3): e1005490. doi:10.1371/journal.ppat.1005490. http://dx.doi.org/10.1371/journal.ppat.1005490.1553-7366http://nrs.harvard.edu/urn-3:HUL.InstRepos:26318699While 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.en-USBiology and Life SciencesCell BiologyCellular TypesAnimal CellsBlood CellsWhite Blood CellsT CellsImmune CellsImmunologyMedicine and Health SciencesOrganismsBacteriaActinobacteriaMycobacterium TuberculosisBiology and life sciencesCell biologyCellular typesAnimal cellsBlood cellsWhite blood cellsT cellsCytotoxic T cellsImmune cellsMedicine and health sciencesImmune System ProteinsImmune ReceptorsT Cell ReceptorsBiochemistryProteinsSignal TransductionSignal transductionCoreceptorsCD coreceptorsPhysiologyImmune PhysiologyCytokinesImmune SystemInnate Immune SystemDevelopmental BiologyMolecular DevelopmentInfectious DiseasesBacterial DiseasesTuberculosisTropical DiseasesImmunityCell-Mediated ImmunityJournal Article2016-04-0110.1371/journal.ppat.1005490