Vijay K. Kuchroo
Brigham and Women's Hospital
Center for Neurological Diseases, HIM Rm. 786
77 Ave. Louis Pasteur
Boston, MA 02115
The major focus of research in the laboratory is the study of the autoimmune T cell response. Particular focus is given to elucidating the role of different CD4+ T helper subsets in disease, role of costimulatory molecules and their receptors in the activation and differentiation of T cells, role of the Tim molecules in regulating T cell responses, and identification of the mechanisms of protection associated with genetic intervals that confer resistance to autoimmunity.
Aside from Th1 cells, it is now appreciated that other T cell subsets such as IL-17-secreting Th17 cells, IL-9/IL-10-secreting Th9 cells, and IL-10-secreting Tr1 cells can have a major influence on autoimmunity. Our laboratory was among the first to describe the differentiation factors that induce the differentiation of naïve T cells into Th17 cells, Th9 cells and Tr1 cells. Specifically, our laboratory demonstrated that a combination of pro- and anti-inflammatory cytokines, IL-6 and TGF-b, induce differentiation of Th17 cells from naive T cells (1). In addition, our laboratory identified that Th17 cells produce IL-21, which further amplifies the generation of Th17 cells (2). We have recently identified IL-27 as a major inducer of Tr1 cells both in vitro and in vivo (3). We have shown that IL-27-induced Tr1 cells contribute to prevention of autoimmune inflammation, principally in Experimental autoimmune encephalomyelitis (EAE), a mouse model of human Multiple sclerosis (MS). We are currently investigating the molecular mechanisms that are responsible for the development of Th1and Tr1 cells in order to assess their potential in the treatment of human autoimmune diseases. Using expression profiling during Th17 and Tr1 differentiation, we have identified key steps in the differentiation of this novel T cell subset.
Our laboratory identified TIM (T cell Immunoglobulin and Mucin)-3 as a cell surface molecule expressed only on Th1 cells but not other Th cell types. The identification of Tim-3 led to the discovery of the TIM family of molecules, which includes Tim-1, Tim-2, Tim-3 and Tim-4. Tim-3 is a negative receptor. Negative receptors serve to ensure contraction of antigen-specific lymphocytes during an immune response and defects in negative receptors are implicated in the pathogenesis of autoimmune diseases such as MS. We have now shown that Tim-3 is expressed on exhausted T cells n chronic viral infections and Tumor infiltrating lymphocytes (TILs) that exhibit an exhausted phenotype (4). Currently we are studying the mechanistic role of Tim-3 in T cell exhaustion in cancer and in chronic viral infections.
Many genetic loci that are linked to disease susceptibility and resistance have been identified in genome wide scans. Examination of the genes in one of these loci has led to the identification of several alternate splice variants of the costimulatory molecule CTLA-4 (5). How expression of different CTLA-4 splice variants as well as other costimulatory molecules affect the responses of T cells that recognize myelin autoantigens is an ongoing research effort.
Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, Weiner HL, Kuchroo VK. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 2006 May 11;441(7090):235-8. Epub 2006 Apr 30.
Korn T, Bettelli E, Gao W, Awasthi A, Jager A, Strom TB, Oukka M, Kuchroo VK. IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature. 2007 Jul 26;448(7152):484-7. Epub 2007 Jun 20.
Awasthi A, Carrier Y, Peron JP, Bettelli E, Kamanaka M, Flavell RA, Kuchroo VK, Oukka M, Weiner HL. A dominant function for interleukin 27 in generating interleukin 10-producing anti-inflammatory T cells. Nat Immunol. 2007; 8(12):1380-9.
Sakuishi K, Apetoh L, Sullivan JM, Blazer BR, Kuchroo VK, Anderson AC. Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J Exp Med. 2010 Sep 27;207(10):2187-94. PMCID: PMC2947065
Monney L, Sabatos CA, Gaglia JL, Ryu A, Waldner H, Chernova T, Manning S, Greenfield EA, Coyle AJ, Sobel RA, Freeman GJ, Kuchroo VK. Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature. 2002 Jan 31;415(6871):536-41.
Last Update: 1/6/2014