title: TIM3 Mediates T Cell Exhaustion during Mycobacterium tuberculosis Infection.
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.
authors.affiliation: Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Pushpa
authors.initials: P
authors.lastname: Jayaraman
authors.affiliation: Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Miye K
authors.initials: MK
authors.lastname: Jacques
authors.affiliation: Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Chen
authors.initials: C
authors.lastname: Zhu
authors.affiliation: Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Steblenko
authors.affiliation: Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Britni L
authors.initials: BL
authors.lastname: Stowell
authors.affiliation: Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Asaf
authors.initials: A
authors.lastname: Madi
authors.affiliation: Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Ana C
authors.initials: AC
authors.lastname: Anderson
authors.affiliation: Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Kuchroo
authors.affiliation: Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Samuel M
authors.initials: SM
authors.lastname: Behar
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D007109:Immunity; D016753:Interleukin-10 / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D051379:Mice; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D011991:Receptors, Virus / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology*; D014376:Tuberculosis / Q000276:immunology*
chemical_list: C442241:Havcr2 protein, mouse; D000072597:Hepatitis A Virus Cellular Receptor 2; C556062:IL10 protein, mouse; D007376:Interleukin-2; D011991:Receptors, Virus; D016753:Interleukin-10