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The Journal of Immunology, 2004, 172: 4686-4690.
Copyright © 2004 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: Ligation of the Glucocorticoid-Induced TNF Receptor Enhances Autoreactive CD4+ T Cell Activation and Experimental Autoimmune Encephalomyelitis1

Adam P. Kohm, Julie S. Williams and Stephen D. Miller2

Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611

The glucocorticoid-induced TNFR (GITR) is expressed at high levels on resting CD4+CD25+ T regulatory (TR) cells and regulates their suppressive phenotype. Accordingly, we show that anti-GITR mAb treatment of SJL mice with proteolipid protein 139–151-induced experimental autoimmune encephalomyelitis significantly exacerbated clinical disease severity and CNS inflammation, and induced elevated levels of Ag-specific T cell proliferation and cytokine production. Interestingly, prior depletion of TR cells failed to result in exacerbated experimental autoimmune encephalomyelitis suggesting alternative targets for the anti-GITR mAb treatment. Importantly, naive CD4+CD25− T cells up-regulated GITR expression in an activation-dependent manner and anti-GITR mAb treatment enhanced the level of CD4+ T cell activation, proliferation, and cytokine production in the absence of TR cells both in vivo and in vitro. Taken together, these findings suggest a dual functional role for GITR as GITR cross-linking both inactivates TR cells and increases CD4+CD25− T cell effector function, thus enhancing T cell immunity.




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