GITR triggering induces expansion of both effector and regulatory CD4+ T cells in vivo.
Glucocorticoid-induced TNF receptor family-related protein (GITR) is expressed on activated and regulatory T cells, but its role on these functionally opposing cell types is not fully understood. Here we describe that transgenic expression of GITR's unique ligand (GITRL) induces a prominent increase of both effector and regulatory CD4(+) T cells, but not CD8(+) T cells. Regulatory T cells from GITRL transgenic mice are phenotypically activated and retain their suppressive capacity. The accumulation of effector and regulatory T cells is not due to enhanced differentiation of naive T cells, but is a direct result of increased proliferation. Functional consequences of increased numbers of both regulatory and effector T cells were tested in an autoimmune model and show that GITR stimulation is protective, as it significantly delays disease induction. These data indicate that GITR regulates the balance between regulatory and effector CD4(+) T cells by enhancing proliferation of both populations in parallel.
van Olffen
Ronald W
RW
Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Koning
Nathalie
N
van Gisbergen
Klaas P J M
KP
Wensveen
Felix M
FM
Hoek
Robert M
RM
Boon
Louis
L
Hamann
Jörg
J
van Lier
Rene A W
RA
Nolte
Martijn A
MA
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005260:Female; D053450:Glucocorticoid-Induced TNFR-Related Protein; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology; D007376:Interleukin-2 / Q000096:biosynthesis / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017475:Receptors, Nerve Growth Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D053450:Glucocorticoid-Induced TNFR-Related Protein; D007376:Interleukin-2; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C106544:Tnfrsf18 protein, mouse