Roles of cytotoxic T-lymphocyte-associated antigen-4 in the inductive phase of oral tolerance.
To elucidate the roles of cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) in oral tolerance, we studied the consequences of CTLA-4 blockade during the inductive phase of oral tolerance using a transgenic T-cell transfer model. We found that CTLA-4 blockade significantly accelerated cell cycle progression of antigen-specific T cells and dramatically increased their numbers in lymphoid organs following oral administration of ovalbumin (OVA). In mice fed with OVA, only approximately 35% of specific T cells underwent more than four cycles of cell division. This was increased to 65% in mice fed with OVA and treated with a blocking anti-CTLA-4 monoclonal antibody (mAb). The OVA-specific T cells in the latter group were localized primarily in the T-cell zones of the mesenteric lymph nodes and Peyer's patches with a few penetrated into B-cell follicles. Nevertheless, both faecal anti-OVA immunoglobulin A (IgA) and seral anti-OVA immunoglobulin G (IgG) were produced in anti-CTLA-4 mAb-treated mice. These results suggest that CTLA-4 limits the degree of T-cell activation by blocking cell cycle progression during the inductive phase of oral tolerance. In the absence of the CTLA-4 signal, mucosal exposure of antigen induces heightened T-cell activation and expansion, which in turn promotes the production of antigen-specific antibodies.
Chen
Yiguang
Y
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, 421 Curie Blvd., Philadelphia, PA 19104, USA.
Ma
Yuanfang
Y
Chen
Youhai
Y
D000069594:Abatacept; D000284:Administration, Oral; D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000941:Antigens / Q000008:administration & dosage; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D060908:CTLA-4 Antigen; D002453:Cell Cycle / Q000276:immunology; D002478:Cells, Cultured; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D007108:Immune Tolerance / Q000276:immunology*; D018928:Immunity, Mucosal; D018796:Immunoconjugates; D007070:Immunoglobulin A / Q000096:biosynthesis; D007074:Immunoglobulin G / Q000096:biosynthesis; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000008:administration & dosage; D010581:Peyer's Patches / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
D000911:Antibodies, Monoclonal; D000941:Antigens; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018984:Epitopes, T-Lymphocyte; D018796:Immunoconjugates; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D000069594:Abatacept; D010047:Ovalbumin