In 2002, we cloned Tim-3 as a molecule differentially expressed of IFN?-producing Th1/Tc1 cells. However, we have found that Tim-3 is also expressed on pro-inflammatory Th17 cells. Subsequently, we identified Galectin- 9 as the Tim-3 ligand and found that the Galectin-9/Tim-3 interaction led to cell death and termination of Th1/Tc1 responses. These studies, together with other in vivo blockade studies with soluble Tim-3, suggested that Tim-3 is an inhibitory molecule that dampens effector Th1/Tc1 responses. Exciting new data suggest that Tim-3 is also involved in inducing T cell exhaustion. Tim-3 expression is increased on effector T cells in chronic viral infections (HIV, HCV) and cancers, rendering them dysfunctional. However, in human autoimmune diseases there is loss of Tim-3 expression on effector T cells, making them highly proinflammatory and pathogenic. Therefore, Tim-3 plays a central regulatory role in multiple human diseases yet very little is known about the functional biology of Tim-3. It is not clear what induces Tim-3 expression on T cells and how it mediates its inhibitory effects. We have made a novel observation that IL-27, an immunosuppressive cytokine, is a potent inducer of Tim-3 expression on T cells. To understand the intracellular pathways that mediate Tim-3 function, we undertook a yeast two-hybrid screen and identified Bat3 (HLA-B associated transcript 3) as a molecule that binds to the Tim-3 cytoplasmic tail. Based on our preliminary data, we hypothesize that IL-27 produced during the resolution phase of autoimmune diseases induces Tim-3 expression on effector T cells to promote T cell death/exhaustion and resolve tissue inflammation and that Bat3, when bound to the Tim-3 tail, acts as a molecular """"""""gate-keeper"""""""" that regulates the inhibitory function of Tim-3. To address this hypothesis we propose two specific aims: 1) Analyze the molecular mechanisms by which Tim-3 is induced on effector T cells. We have found that IL-27 induces the transcription factor NFIL3, which may be involved in Tim-3 expression. Using NFIL3-/- mice, we will determine whether the IL-27/NFIL3/Tim-3 axis is critical for the development of experimental autoimmune encephalomyelitis (EAE) and induction of T cell exhaustion/dysfunction. 2) Identify the molecular mechanisms by which Tim-3 signals into T cells to induce T cell dysfunction/exhaustion and inhibit EAE. Since we have identified Bat3 as a binding partner for the Tim-3 tail, we will analyze whether conditional loss of Bat-3 in T cells induces T cell dysfunction and study how Bat3 bound to Tim-3 regulates proximal CD3-TcR signaling. The proposed studies will identify the molecular mechanisms by which Tim-3 mediates its inhibitory function, which could be exploited to dampen pathogenic T cells in autoimmune diseases.
Tim-3:galectin-9 pathway has emerged as an important player in inducing T cell inhibition/exhaustion in effector T cells in chronic human viral infectios like HIV and HCV. In contrast in a number of human autoimmune diseases including multiple sclerosis, Psoriasis, Rheumatoid arthritis and type 1 diabetes, there is evidence that Tim-3 is functioning suboptimally resulting in generation of highly pathogenic effector T cells. This proposal will provide a greater understanding of how Tim-3 can be induced and how it functions in effector T cells so that the pathway can be therapeutically exploited in chronic viral infection, cancers and autoimmune diseases.
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| Wu, Chuan; Chen, Zuojia; Xiao, Sheng et al. (2018) SGK1 Governs the Reciprocal Development of Th17 and Regulatory T Cells. Cell Rep 22:653-665 |
| Joller, Nicole; Kuchroo, Vijay K (2017) Tim-3, Lag-3, and TIGIT. Curr Top Microbiol Immunol 410:127-156 |
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| Karwacz, Katarzyna; Miraldi, Emily R; Pokrovskii, Maria et al. (2017) Critical role of IRF1 and BATF in forming chromatin landscape during type 1 regulatory cell differentiation. Nat Immunol 18:412-421 |
| Das, Madhumita; Zhu, Chen; Kuchroo, Vijay K (2017) Tim-3 and its role in regulating anti-tumor immunity. Immunol Rev 276:97-111 |
| Wu, Chuan; Chen, Zuojia; Dardalhon, Valerie et al. (2017) The transcription factor musculin promotes the unidirectional development of peripheral Treg cells by suppressing the TH2 transcriptional program. Nat Immunol 18:344-353 |
| Jayaraman, Pushpa; Jacques, Miye K; Zhu, Chen et al. (2016) TIM3 Mediates T Cell Exhaustion during Mycobacterium tuberculosis Infection. PLoS Pathog 12:e1005490 |
| Singer, Meromit; Wang, Chao; Cong, Le et al. (2016) A Distinct Gene Module for Dysfunction Uncoupled from Activation in Tumor-Infiltrating T Cells. Cell 166:1500-1511.e9 |
| Chihara, Norio; Madi, Asaf; Karwacz, Katarzyna et al. (2016) Differentiation and Characterization of Tr1 Cells. Curr Protoc Immunol 113:3.27.1-3.27.10 |
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