Cutting edge: the natural ligand for glucocorticoid-induced TNF receptor-related protein abrogates regulatory T cell suppression.
CD4(+)25(+) regulatory T (Treg) cells maintain immunological self-tolerance through mechanisms that are only in part understood. Previous studies suggest that the glucocorticoid-induced TNFR-related protein (GITR), which is preferentially expressed on the surface of Treg cells, potentially provides a signal that abrogates Treg suppression. In this study, we show that a soluble form of mouse GITR ligand (sGITR-L) induces GITR-dependent NF-kappaB activation and blocks in vitro suppression mediated by both resting and preactivated polyclonal and Ag-specific Treg cells. Since sGITR-L along with rIL-2 induces proliferation of CD4(+)25(+) cells, it appears that sGITR-L can break the anergic state of Treg cells. Because sGITR-L also up-regulates IL-2 secretion by activated CD4(+)25 (-)T cells, these two sGITR-L induced signals synergize to interfere with suppressor activity by CD4(+)25(+) Treg cells.
Ji
Hong-bin
HB
Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Liao
Gongxian
G
Faubion
William A
WA
Abadía-Molina
Ana C
AC
Cozzo
Cristina
C
Laroux
F Stephen
FS
Caton
Andrew
A
Terhorst
Cox
C
D000276:Adjuvants, Immunologic / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism / Q000502:physiology*; D002455:Cell Division / Q000276:immunology; D002460:Cell Line; D017635:Clonal Anergy / Q000276:immunology*; D053450:Glucocorticoid-Induced TNFR-Related Protein; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism / Q000502:physiology; D007399:Interphase / Q000276:immunology; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D012995:Solubility; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D048069:Tumor Necrosis Factors; D015854:Up-Regulation / Q000276:immunology
D000276:Adjuvants, Immunologic; D002352:Carrier Proteins; D053450:Glucocorticoid-Induced TNFR-Related Protein; D007376:Interleukin-2; D008024:Ligands; D016328:NF-kappa B; 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