title: Roles of CD28, CTLA4, and inducible costimulator in acute graft-versus-host disease in mice.
abstract: T cells deficient for CD28 have reduced ability to expand and survive, but still cause graft-versus-host disease (GVHD). Inducible costimulator (ICOS), a member of the CD28 family, is expressed on antigen-activated T cells and plays unique roles in T cell activation and effector function. We hypothesized that ICOS contributes to the development of GVHD in the absence of B7:CD28/CTLA4 costimulation. In this study, we evaluated the roles of CD28, CTLA4, and ICOS in the pathogenesis of acute GVHD after myeloablative allogeneic bone marrow transplantation. Unexpectedly, we found that blocking CD28 and CTLA4 signals using the clinically relevant reagent CTLA4-Ig increases the severity of GVHD mediated by CD4(+) T cells, and that such treatment does not add any benefit to the blockade of ICOS. In contrast, selectively blocking CD28 and ICOS, but not CTLA4, prevents GVHD more effectively than blocking either CD28 or ICOS alone. Taken together, these results indicate that CD28 and ICOS are synergistic in promoting GVHD, whereas the CTLA4 signal is required for T cell tolerance regardless of ICOS signaling. Thus, blocking CD28 and ICOS while sparing CTLA4 represents a promising approach for abrogating pathogenic T cell responses after allogeneic bone marrow transplantation.
authors: Department of Hematology, Xiangya Hospital Central South University, Changsha, Hunan, China.
authors: Jun
authors: J
authors: Li
authors: Kenrick
authors: K
authors: Semple
authors: Woong-Kyung
authors: WK
authors: Suh
authors: Chen
authors: C
authors: Liu
authors: Fangping
authors: F
authors: Chen
authors: Bruce R
authors: BR
authors: Blazar
authors: Xue-Zhong
authors: XZ
authors: Yu
mesh_terms: D000069594:Abatacept; D000208:Acute Disease; D000818:Animals; D015703:Antigens, CD / Q000276:immunology*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology*; D018122:B7-1 Antigen / Q000276:immunology; D051940:B7-2 Antigen / Q000276:immunology; D016026:Bone Marrow Transplantation / Q000009:adverse effects*; D018106:CD28 Antigens / Q000276:immunology*; D060908:CTLA-4 Antigen; D053222:Fas Ligand Protein / Q000096:biosynthesis; D006086:Graft vs Host Disease / Q000209:etiology / Q000276:immunology* / Q000517:prevention & control; D007108:Immune Tolerance / Q000276:immunology; D018796:Immunoconjugates / Q000494:pharmacology / Q000627:therapeutic use; D060889:Inducible T-Cell Co-Stimulator Protein; D007371:Interferon-gamma / Q000096:biosynthesis; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011828:Radiation Chimera; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D014184:Transplantation, Homologous / Q000009:adverse effects; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; C556694:Icos protein, mouse; D018796:Immunoconjugates; D060889:Inducible T-Cell Co-Stimulator Protein; D014409:Tumor Necrosis Factor-alpha; D000069594:Abatacept; D007371:Interferon-gamma