GITR ligand-costimulation activates effector and regulatory functions of CD4+ T cells.
Engagement of glucocorticoid-induced TNFR-related protein (GITR) enables the costimulation of both CD25(-)CD4(+) effector (Teff) and CD25(+)CD4(+) regulatory (Treg) cells; however, the effects of GITR-costimulation on Treg function remain controversial. In this study, we examined the effects of GITR ligand (GITRL) binding on the respective functions of CD4(+) T cells. GITRL-P815 transfectants efficiently augmented anti-CD3-induced proliferation and cytokine production by Teff cells. Proliferation and IL-10 production in Treg were also enhanced by GITRL transfectants when exogenous IL-2 and stronger CD3 stimulation was provided. Concomitant GITRL-costimulation of Teff and Treg converted the anergic state of Treg into a proliferating state, maintaining and augmenting their function. Thus, GITRL-costimulation augments both effector and regulatory functions of CD4(+) T cells. Our results suggest that highly activated and increased ratios of Treg reverse the immune-enhancing effects of GITRL-costimulation in Teff, which may be problematic for therapeutic applications using strong GITR agonists.
Igarashi
Hanna
H
Department of Molecular Immunology, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8549, Japan.
Cao
Yujia
Y
Iwai
Hideyuki
H
Piao
Jinhua
J
Kamimura
Yosuke
Y
Hashiguchi
Masaaki
M
Amagasa
Teruo
T
Azuma
Miyuki
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D000938:Antigen-Presenting Cells / Q000276:immunology; D017252:CD3 Complex / Q000378:metabolism; D015704:CD4 Antigens / Q000032:analysis; D018920:Coculture Techniques; D005260:Female; D016753:Interleukin-10 / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis; D008024:Ligands; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D014162:Transfection; D048069:Tumor Necrosis Factors / Q000819:agonists* / Q000235:genetics
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D015704:CD4 Antigens; D053645:Interleukin-2 Receptor alpha Subunit; D008024:Ligands; C478966:Tnfsf18 protein, mouse; D048069:Tumor Necrosis Factors; D016753:Interleukin-10