DF/HCC Program Affiliation

Cancer Immunology

Research Abstract

Our group is interested in understanding the molecular and cellular elements responsible for self tolerance and prevention of autoimmune disease.

Not all self reactive T cells are deleted in the thymus. We have defined inhibitory interactions between regulatory CD4 and CD8 T cell subsets and immunological effector cells that serve to maintain self tolerance in the face of chronic infectious stimuli. Recent studies have shown that expression of the MHC class Ib molecule, Qa-1, by CD4+ cells protects them from NK lysis due to an interaction between Qa-1–Qdm and CD94–NKG2A on NK cells.

We have also defined a new molecular link in the death pathway that eliminates self-reactive cells in the thymus. Biochemical and genetic studies uncovered the role of a novel serine kinase termed MINK that bridges signals from autoreactive T cell receptors to cellular apoptosis.

Failure of intrathymic deletion and regulatory interactions can lead to autoimmune diseases, including Systemic Lupus Erythematosus (SLE) and a murine model of Multiple Sclerosis. We have defined a gene - Osteopontin (Opn) that, when dysregulated, may play a key role in this pathogenic process. Secreted Opn (Opn-s) is essential for the development of IFN-gamma-producing Th1 cells, while intracellular Opn (Opn-i) is essential for expression of Type I IFN by pDC. Analysis of mutant mice lacking the two Opn isoforms will test the role of Opn in animal models of autoimmune diease, while definition of the Opn response in a test tube may allow identification of small molecules that can inhibit this process.

Publications

• Lu L, Ikizawa K, Hu D, Werneck MB, Wucherpfennig KW, Cantor H.Regulation of Activated CD4(+) T Cells by NK Cells via the Qa-1-NKG2A Inhibitory Pathway.Immunity 2007 May 15.
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• Shinohara ML, Lu L, Bu J, Werneck MB, Kobayashi KS, Glimcher LH, Cantor H.Osteopontin expression is essential for interferon-alpha production by plasmacytoid dendritic cells.Nat Immunol 2006 May;7(5):498-506.
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• Shinohara ML, Jansson M, Hwang ES, Werneck MB, Glimcher LH, Cantor H.T-bet-dependent expression of osteopontin contributes to T cell polarization.Proc Natl Acad Sci U S A 2005 Nov 14.
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• McCarty N, Paust S, Ikizawa K, Dan I, Li X, Cantor H.Signaling by the kinase MINK is essential in the negative selection of autoreactive thymocytes.Nat Immunol 2005 Jan;6(1):65-72.
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• Hu D, Ikizawa K, Lu L, Sanchirico ME, Shinohara ML, Cantor H.Analysis of regulatory CD8 T cells in Qa-1-deficient mice.Nat Immunol 2004 May;5(5):516-23.
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• Panoutsakopoulou V, Sanchirico ME, Huster KM, Jansson M, Granucci F, Shim DJ, Wucherpfennig KW, Cantor H.Analysis of the relationship between viral infection and autoimmune disease.Immunity 2001 Jul;15(1):137-47.
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