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The laboratory has primarily focused on studying the autoimmune immune response to the proteins of the CNS myelin namely myelin proteolipid protein (PLP) and myelin Oligodendrocyte glycoprotein (MOG) (1, 2). T cell receptor (TcR) transgenic mice that express TcRs that recognize two different myelin antigens, PLP and MOG have been generated (1, 2). The transgenic mice develop spontaneous autoimmune disease of the central nervous system, called experimental autoimmune encephalomyelitis (EAE), a mouse model for human disease multiple sclerosis (MS). Whereas the PLP TcR transgenic mice develop a relapsing-remitting disease (1), the MOG TcR transgenic mice develop spontaneous optic neuritis often the first sign of disease in MS patients (2). Class II tetramers tethered with myelin peptides have also been generated (3). Using these reagents, the T cell response to the encephalitogenic determinants of PLP in H-2 congenic mice has been analyzed.
Genetic basis for the disease susceptibility and resistance has been analyzed by identifying genetic loci by genome wide scans, generation of congenic mice and identifying genes within these congenic intervals (4, 5). Special emphasis has been put on identifying common genetic elements that affect susceptibility to multiple autoimmune diseases with special focus on EAE and type 1 diabetes in the NOD mice (4). This genetic analysis for autoimmune susceptibility resulted in the identification various loci that affect susceptibility to both EAE and diabetes. Using this approach an alternate spliced form of CTLA4 called ligand independent CTLA4 (liCTLA4), has been identified which is highly expressed in resistant strains of mice (5). Since autoimmune susceptible strains appear genetically deficient in the liCTLA4, transgenic mice expressing liCTLA4 have been generated to address the in vivo role of liCTLA4 in regulation of T cell responses and autoimmunity.
Since Th1 cells are generally involved in the induction of autoimmune diseases, we have generated a panel of monoclonal antibodies that identify cell surface molecules expressed only on Th1 cells but not on Th2 cells. One of these monoclonal antibodies identified a novel gene family called TIM (T cell Immunoglobulin and Mucin) gene family (6). Whereas TIM-3 is expressed on differentiated Th1 cells, the TIM-2 molecule is expressed exclusively on Th2 cells. TIM-4, another member of TIM gene family is predominantly expressed on dendritic cells. These cell surface molecules regulate expansion and functions of terminally differentiated Th1 and Th2 cells and also in the induction of peripheral tolerance (7). The ligands for the Tim-1 and Tim-3 have been molecularly cloned and the functional effects of their binding to the receptors is being currently investigated by using transgenic and knockout approaches.
1. Waldner H, Whitters MJ, Sobel RA, Collins M, Kuchroo VK. Fulminant spontaneous autoimmunity of the central nervous system in mice transgenic for the myelin proteolipid protein-specific T cell receptor. Proc Natl Acad Sci U S A. 2000 Mar 28;97(7):3412-7.
2. Bettelli E, Pagany M, Weiner HL, Linington C, Sobel RA, Kuchroo VK.
3. Reddy J, Illes Z, Zhang X, Encinas J, Pyrdol J, Nicholson L, Sobel RA, Wucherpfennig KW, Kuchroo VK. Myelin proteolipid protein-specific CD4+CD25+ regulatory cells mediate genetic resistance to experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A. 2004 Oct 26;101(43):15434-9.
4. Encinas JA, Wicker LS, Peterson LB, Mukasa A, Teuscher C, Sobel R, Weiner HL, Seidman CE, Seidman JG, Kuchroo VK. QTL influencing autoimmune diabetes and encephalomyelitis map to a 0.15-cM region containing Il2. Nat Genet. 1999 21:158-60.
5. Vijayakrishnan L, Slavik JM, Illes Z, Greenwald RJ, Rainbow D, Greve B, Peterson LB, Hafler DA, Freeman GJ, Sharpe AH, Wicker LS, Kuchroo VK.
6. 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.
7. Sabatos CA, Chakravarti S, Cha E, Schubart A, Sanchez-Fueyo A, Zheng XX, Coyle AJ, Strom TB, Freeman GJ, Kuchroo VK. Interaction of Tim-3 and Tim-3 ligand regulates T helper type 1 responses and induction of peripheral tolerance. Nature Immunol. 2003 Nov;4(11):1102-10.