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NFB-Inducing Kinase Deficiency Results in the Development of a Subset of Regulatory T Cells, which Shows a Hyperproliferative Activity upon Glucocorticoid-Induced TNF Receptor Family-Related Gene Stimulation¹

Department of Microbiology and Immunology, Dartmouth Medical School and the Norris Cotton Cancer Center, Lebanon, NH 03756

CD4⁺CD25⁺ regulatory T cells (T^reg) play an important role in maintaining immunologic tolerance. Glucocorticoid-induced TNFR family-related gene (GITR) expressed preferentially at high levels on T^reg has been shown to be a key player of regulating T^reg-mediated suppression. A recent study reports that NF-B-inducing kinase (NIK) expression in thymic stroma is important for the normal production of T^reg but not for its suppression capacity. In this report, we have shown that T^reg from NIK-deficient mice display hyperproliferative activities upon GITR stimulation through an IL-2-independent mechanism. Furthermore, high dose IL-2, anti-CD28 stimulation, or GITR ligand-transduced bone marrow-derived dendritic cells used as APC (culture conditions which drive T^reg proliferation in vitro) could not ablate this difference in proliferative activity between NIK-deficient and wild-type T^reg. Additional experiments have shown NIK-deficient mice have a higher ratio of CD4⁺CD25⁺CD62L^low T^reg both in thymus and periphery than their wild-type littermates. This CD62^low subset is responsible for the hyperproliferative activity upon GITR stimulation. These data suggest a novel role of NIK in controlling the development and expansion of CD4⁺CD25⁺ regulatory T cells.

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