Mycobacterium tuberculosis infection is one of the leading causes of mortality worldwide. One third of the population is estimated to be infected, however only 5-10% of those individuals can transmit the disease. While T cell immunity initially limits mycobacterium growth, it is unclear why T cell immunity fails to sterilize the infection and prevent subsequent recrudescence. One hypothesis is T cell exhaustion is mediating the failure of T cell immunity late during infection. Here we show the development of T cell exhaustion during chronic infection, and that the inhibitory receptor T cell-immunoglobulin and mucin domain containing 3 (TIM3) mediates the development of T cell exhaustion. TIM3 accumulates on the surface of T cells throughout the course of infection and there is a subsequent decrease in effector cytokine production, such as IL-2, TNFα, and IFNγ. Furthermore, antibody blockade of TIM3 restores T cell function and improves bacterial control. Our results show that TIM3 is mediating T cell exhaustion during chronic TB infection and leading to suboptimal bacterial control.
| Identifer | oai:union.ndltd.org:umassmed.edu/oai:escholarship.umassmed.edu:gsbs_diss-1916 |
| Date | 07 July 2017 |
| Creators | Jacques, Miye K. |
| Publisher | eScholarship@UMassChan |
| Source Sets | University of Massachusetts Medical School |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | Morningside Graduate School of Biomedical Sciences Dissertations and Theses |
| Rights | Licensed under a Creative Commons license, http://creativecommons.org/licenses/by-nc/4.0/ |
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