Vijay K. Kuchroo
Professor of Neurology
Center for Neurologic Diseases
Brigham and Women's Hospital
HIM Room 786
77 Avenue Louis Pasteur
Boston, MA 02115
9 Postdoctoral Fellows, 1 Graduate Student
The major focus of research in the laboratory is to study the autoimmune T cell response, role of costimulatory molecules and their receptors in the induction and differentiation of T cells and identification of cell surface molecules differentially expressed on T cell subsets.
The laboratory has primarily focused on studying the autoimmune response to the proteins of 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 many MS patients (2). Class II tetramers carrying self-myelin peptides have also been generated (3). Using these tetramers, the T cell response to the encephalitogenic determinants of PLP in H-2 congenic mice has been analyzed. While some strains of mice are highly susceptible, other H-2 congenic strains are resistant to the development of disease. The genetic basis of disease susceptibility and resistance has been analyzed by identifying genetic loci by genome wide scans and by identifying genes within these congenic intervals (4, 5). This genetic analysis for autoimmune susceptibility resulted in the identification of an alternate spliced form of CTLA4 called ligand independent CTLA4 (liCTLA4), which is highly expressed in resistant individuals (5).
Since Th1 cells are generally involved in the induction of organ specific autoimmune diseases, the laboratory has developed 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 only on Th2 cells. The other member, TIM-4, is predominantly expressed on dendritic cells. These cell surface molecules regulate expansion and functions of Th1 and Th2 cells and also induction of peripheral tolerance (7). The TIM molecules appear to play a crucial role in regulating the functions of terminally differentiated Th1 and Th2 cells. The ligands for the Tim molecules are being cloned and the functional effects of their binding to the receptors is being actively investigated by using transgenic and knock-out approaches.
In addition to Th1 cells, another subset of T cells called Th17 distinct from Th1 and Th2 cells was shown to play a crucial role in the induction of many autoimmune diseases. Previous studies had suggested that IL-23 is the differentiation factor for the induction of Th17 cells but our recent studies (8) have shown that TGFβ and IL-6 act in concert to differentiate Th17 cells. Our studies demonstrate a dichotomy between CD4+, CD25+ regulatory T cells and highly pathogenic Th17 cells T cells. The signaling pathways and cell surface molecules that are differentially expressed in regulatory and Th17 effector cells is currently being investigated.
- 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;441:235-8.
- 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.
- Vijayakrishnan L, Slavik JM, Illes Z, Greenwald RJ, Rainbow D, Greve B, Peterson LB, Hafler DA, Freeman GJ, Sharpe AH, Wicker LS, Kuchroo VK. An autoimmune disease-associated CTLA-4 splice variant lacking the B7 binding domain signals negatively in T cells. Immunity. 2004 May;20(5):563-75.
- 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.
- 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.
Immunology webpage updated 12/02/2009