Engagement of glucocorticoid-induced TNFR family-related receptor on effector T cells by its ligand mediates resistance to suppression by CD4+CD25+ T cells.
Nonactivated CD4+CD25+ regulatory T cells constitutively express glucocorticoid-induced TNFR family-related receptor (GITR), a TNFR family member whose engagement was presumed to abrogate regulatory T cell-mediated suppression. Using GITR-/- mice, we report that GITR engagement on CD25-, not CD25+ T cells abrogates T cell-mediated suppression. Mouse APCs constitutively express GITR ligand (GITR-L), which is down-regulated following TLR signaling in vivo. Although GITR-/-CD25- T cells were capable of mounting proliferative responses, they were incapable of proliferation in the presence of physiological numbers of CD25+ T cells. Thus, GITR-L provides an important signal for CD25- T cells, rendering them resistant to CD25+ -mediated regulation at the initiation of the immune response. The down-regulation of GITR-L by inflammatory stimuli may enhance the susceptibility of effector T cells to suppressor activity during the course of an infectious insult.
Cellular Immunology Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Geoffrey L
GL
Stephens
Rebecca S
RS
McHugh
Matthew J
MJ
Whitters
Deborah A
DA
Young
Deborah
D
Luxenberg
Beatriz M
BM
Carreno
Mary
M
Collins
Ethan M
EM
Shevach
D000818:Animals; D018106:CD28 Antigens / Q000502:physiology; D015704:CD4 Antigens / Q000032:analysis*; D002352:Carrier Proteins / Q000502:physiology*; D053450:Glucocorticoid-Induced TNFR-Related Protein; D006801:Humans; D008024:Ligands; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D015375:Receptors, Interleukin-2 / Q000032:analysis*; D017475:Receptors, Nerve Growth Factor / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*; D048069:Tumor Necrosis Factors
D018106:CD28 Antigens; D015704:CD4 Antigens; D002352:Carrier Proteins; D053450:Glucocorticoid-Induced TNFR-Related Protein; D008024:Ligands; D015375:Receptors, Interleukin-2; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C491405:TNFRSF18 protein, human; C106544:Tnfrsf18 protein, mouse; C478966:Tnfsf18 protein, mouse; D048069:Tumor Necrosis Factors