- PROJECT 3 Tim-3 modulates immunity to the important human pathogens HIV, HCV, and Mycobacterium tuberculosis (Mtb). The interaction between Tim-3 and its ligands can induce T cell exhaustion: a state characterized by progressive loss of effector functions leading to impairment of T cell mediated immunity. Importantly, reversing T cell exhaustion is a potential therapeutic strategy for the treatment of cancer and chronic viral infection. We have previously shown that the Tim3/Gal9 interaction activates macrophages to suppress intracellular Mtb growth and our new data shows that Tim-3 promotes IFN? production by T cells. We detect two distinct Tim-3+ T cell subsets in the lungs of infected mice: 1) T cells that express Tim-3 but not other exhaustion markers (which we refer to as Tim3+Exh-);and 2) T cells that express Tim3 in combination with other exhaustion markers (Tim3+Exh+). The former subset, which has not been described during chronic viral infection or cancer, behaves as effector T cells in mice with TB. The latter subset appears to be exhausted. Experiments using blocking antibodies or knockout mice to interrupt Tim-3 signaling improves Mtb disease outcome, which suggests that these interventions lead to improved immunity. Thus, two (opposing) paradigms exist for how Tim-3 signaling affects microbial immunity: (1) Tim-3 expression promotes exhaustion of pathogen-specific T cells during chronic infections and cancers;and (2) Tim-3 binding to Gal9 promotes T cell and macrophage antimicrobial activity during acute infection. Our observation that both effector and exhausted T cells express Tim-3 leads us to hypothesize that the the capacity of Tim-3 to positively or negatively regulate immunity is influenced by (a) the cytokines IL-27 and IL-21, which affect its expression;(b) its ligands, Gal-9 and the recently identified CEACAM-1;and (c) other exhaustion molecules that are co- expressed with Tim-3 is co-expressed. We recently identified CEACAM-1 as a second Tim-3 ligand and showed that the trans-interaction between Tim-3 and CEACAM-1 is required to suppress effector T cell function and to maintain T cell tolerance/exhaustion. We will test the hypothesis that the interaction between Tim-3 and its two ligands Gal-9 and CEACAM-1, elicit distinct T cell outcomes. The chronic TB model is perfect for these experiments. Not only is T cell dysfunction believed to play a major role in the pathogenesis of TB, but also we made the novel observation that two distinct Tim3-expressing T cell subsets [Tim3+Exh- and Tim3+Exh+] differ in functions [effector vs. exhausted, respectively]. Therefore, TB provides an important opportunity to identify the mechanism of how Tim-3 ligand selection and the effect of other regulatory signals (e.g., cytokines) affect T cell effector function and dysfunction. The overarching goal of this project is to understand how these factors regulate the dual functions of Tim-3 to modulate its net beneficial or detrimental effect on microbial immunity during chronic infection.

Public Health Relevance

- PROJECT 3 Tuberculosis is the leading cause of death from a bacterial infection and development of new treatment modalities including immunotherapy, vaccines, and antibiotics is a global priority. The factors that allow Mycobacterium tuberculosis to establish chronic infection have not been fully elucidated. The proposed studies will provide critical insight into why the immune system fails to clear the infection and how the T cell response may be re-invigorated as a way to treat chronic infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
2P01AI073748-06A1
Application #
8794863
Study Section
Special Emphasis Panel (ZAI1-PA-I (S1))
Project Start
Project End
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
6
Fiscal Year
2015
Total Cost
$482,447
Indirect Cost
$114,321
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Gautron, Anne-Sophie; Dominguez-Villar, Margarita; de Marcken, Marine et al. (2014) Enhanced suppressor function of TIM-3+ FoxP3+ regulatory T cells. Eur J Immunol 44:2703-11
Joller, Nicole; Lozano, Ester; Burkett, Patrick R et al. (2014) Treg cells expressing the coinhibitory molecule TIGIT selectively inhibit proinflammatory Th1 and Th17 cell responses. Immunity 40:569-81
Thornley, Thomas B; Fang, Zemin; Balasubramanian, Savithri et al. (2014) Fragile TIM-4-expressing tissue resident macrophages are migratory and immunoregulatory. J Clin Invest 124:3443-54
Wu, Chuan; Thalhamer, Theresa; Franca, Rafael F et al. (2014) Galectin-9-CD44 interaction enhances stability and function of adaptive regulatory T cells. Immunity 41:270-82
Ji, Qingyong; Castelli, Luca; Goverman, Joan M (2013) MHC class I-restricted myelin epitopes are cross-presented by Tip-DCs that promote determinant spreading to CD8? T cells. Nat Immunol 14:254-61
Wu, Chuan; Yosef, Nir; Thalhamer, Theresa et al. (2013) Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1. Nature 496:513-7
Carlson, Alicia L; Fujisaki, Joji; Wu, Juwell et al. (2013) Tracking single cells in live animals using a photoconvertible near-infrared cell membrane label. PLoS One 8:e69257
Yosef, Nir; Shalek, Alex K; Gaublomme, Jellert T et al. (2013) Dynamic regulatory network controlling TH17 cell differentiation. Nature 496:461-8
Wu, Chuan; Pot, Caroline; Apetoh, Lionel et al. (2013) Metallothioneins negatively regulate IL-27-induced type 1 regulatory T-cell differentiation. Proc Natl Acad Sci U S A 110:7802-7
Rangachari, Manu; Kuchroo, Vijay K (2013) Using EAE to better understand principles of immune function and autoimmune pathology. J Autoimmun 45:31-9

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