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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS045937-10
Application #
8438835
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Utz, Ursula
Project Start
2003-03-15
Project End
2017-07-31
Budget Start
2012-09-30
Budget End
2013-07-31
Support Year
10
Fiscal Year
2012
Total Cost
$350,447
Indirect Cost
$131,697
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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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
Anderson, Ana C; Joller, Nicole; Kuchroo, Vijay K (2016) Lag-3, Tim-3, and TIGIT: Co-inhibitory Receptors with Specialized Functions in Immune Regulation. Immunity 44:989-1004

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