NF kappa B-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 stimulation.
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-kappaB-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.
Lu
Li-Fan
LF
Department of Microbiology and Immunology, Dartmouth Medical School and Norris Cotton Cancer Center, Lebanon, NH 03756, USA.
Gondek
David C
DC
Scott
Zachary A
ZA
Noelle
Randolph J
RJ
D000818:Animals; D001854:Bone Marrow Cells / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D002461:Cell Line, Transformed; D049109:Cell Proliferation; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D005786:Gene Expression Regulation / Q000276:immunology*; D005822:Genetic Vectors; D053450:Glucocorticoid-Induced TNFR-Related Protein; D007376:Interleukin-2 / Q000502:physiology; D008213:Lymphocyte Activation / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D017475:Receptors, Nerve Growth Factor / Q000235:genetics*; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics*; D050378:T-Lymphocytes, Regulatory / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D014161:Transduction, Genetic; D000097782:NF-kappaB-Inducing Kinase
D053450:Glucocorticoid-Induced TNFR-Related Protein; D007376:Interleukin-2; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D015375:Receptors, Interleukin-2; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; D000097782:NF-kappaB-Inducing Kinase; C106544:Tnfrsf18 protein, mouse