Cutting edge: ligation of the glucocorticoid-induced TNF receptor enhances autoreactive CD4+ T cell activation and experimental autoimmune encephalomyelitis.
The glucocorticoid-induced TNFR (GITR) is expressed at high levels on resting CD4(+)CD25(+) T regulatory (T(R)) 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 T(R) 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 T(R) cells both in vivo and in vitro. Taken together, these findings suggest a dual functional role for GITR as GITR cross-linking both inactivates T(R) cells and increases CD4(+)CD25(-) T cell effector function, thus enhancing T cell immunity.
Kohm
Adam P
AP
Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Williams
Julie S
JS
Miller
Stephen D
SD
D000276:Adjuvants, Immunologic / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D001324:Autoantigens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D002455:Cell Division / Q000276:immunology; D003432:Cross-Linking Reagents / Q000008:administration & dosage; D016207:Cytokines / Q000096:biosynthesis; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D005260:Female; D005938:Glucocorticoids / Q000502:physiology*; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis / Q000276:immunology* / Q000378:metabolism*; D012720:Severity of Illness Index; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism
D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D001324:Autoantigens; D003432:Cross-Linking Reagents; D016207:Cytokines; D005938:Glucocorticoids; D008024:Ligands; D018124:Receptors, Tumor Necrosis Factor