The Journal of Experimental Medicine
Rockland Immunochemicals for Research
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Published online 5 June 2006 doi:10.1084/jem.20060210
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 6, 1413-1418
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BRIEF DEFINITIVE REPORT

 Dysregulated T cell expression of TIM3 in multiple sclerosis

Ken Koguchi, David E. Anderson, Li Yang, Kevin C. O'Connor, Vijay K. Kuchroo, and David A. Hafler

Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115

CORRESPONDENCE David E. Anderson: danderson{at}rics.bwh.harvard.edu

T cell immunoglobulin- and mucin domain–containing molecule (TIM)3 is a T helper cell (Th)1–associated cell surface molecule that regulates Th1 responses and promotes tolerance in mice, but its expression and function in human T cells is unknown. We generated 104 T cell clones from the cerebrospinal fluid (CSF) of six patients with multiple sclerosis (MS) (n = 72) and four control subjects (n = 32) and assessed their cytokine profiles and expression levels of TIM3 and related molecules. MS CSF clones secreted higher amounts of interferon (IFN)-{gamma} than did those from control subjects, but paradoxically expressed lower levels of TIM3 and T-bet. Interleukin 12–mediated polarization of CSF clones induced substantially higher amounts of IFN-{gamma} secretion but lower levels of TIM3 in MS clones relative to control clones, demonstrating that TIM3 expression is dysregulated in MS CSF clones. Reduced levels of TIM3 on MS CSF clones correlated with resistance to tolerance induced by costimulatory blockade. Finally, reduction of TIM3 on ex vivo CD4+ T cells using small interfering (si)RNA enhanced proliferation and IFN-{gamma} secretion, directly demonstrating that TIM3 expression on human T cells regulates proliferation and IFN-{gamma} secretion. Failure to up-regulate T cell expression of TIM3 in inflammatory sites may represent a novel, intrinsic defect that contributes to the pathogenesis of MS and other human autoimmune diseases.

K. Koguchi and D.E. Anderson contributed equally to this work.


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