title: GITR ligand-costimulation activates effector and regulatory functions of CD4+ T cells.
abstract: 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.
authors.affiliation: Department of Molecular Immunology, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8549, Japan.
authors.forename: Hanna
authors.initials: H
authors.lastname: Igarashi
authors.forename: Yujia
authors.initials: Y
authors.lastname: Cao
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Iwai
authors.forename: Jinhua
authors.initials: J
authors.lastname: Piao
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Kamimura
authors.forename: Masaaki
authors.initials: M
authors.lastname: Hashiguchi
authors.forename: Teruo
authors.initials: T
authors.lastname: Amagasa
authors.forename: Miyuki
authors.initials: M
authors.lastname: Azuma
mesh_terms: 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
chemical_list: 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