title: Functional tolerance is maintained despite proliferation of CD4 T cells after encounter with tissue-derived antigen.
abstract: Since negative selection in the thymus is incomplete, some self-reactive T cells are able to mature and seed the periphery. To study how these T cells interact following encounter with the self-protein they recognize in the periphery, we have developed an adoptive transfer system in which HEL-specific TCR transgenic CD4 T cells are transferred to mice expressing HEL protein in the pancreas under the control of the rat insulin promoter. Here we show that after adoptive transfer of HEL-specific T cells functional tolerance is maintained despite evidence that the T cells encounter and respond to pancreas-expressed antigen. Even the provision of an additional activation stimulus by peripheral immunization with HEL protein is insufficient to induce the T cells to cause autoimmune tissue injury. However, in the presence of blocking anti-CTLA-4-mAb, immunized adoptive transfer recipients rapidly developed diabetes. These data suggest that the CTLA-4 pathway regulates the pathogenicity of antigen-specific T cells following a peripheral activation stimulus.
authors.affiliation: Department of Pathology, University of California San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA.
authors.forename: Lara J
authors.initials: LJ
authors.lastname: Ausubel
authors.forename: Anna
authors.initials: A
authors.lastname: Chodos
authors.forename: Nyree
authors.initials: N
authors.lastname: Bekarian
authors.forename: Abul K
authors.initials: AK
authors.lastname: Abbas
authors.forename: Lucy S K
authors.initials: LS
authors.lastname: Walker
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000941:Antigens / Q000276:immunology; D015703:Antigens, CD; D000943:Antigens, Differentiation; D001327:Autoimmune Diseases / Q000276:immunology / Q000503:physiopathology; D001426:Bacterial Proteins / Q000276:immunology* / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D060908:CTLA-4 Antigen; D002352:Carrier Proteins / Q000276:immunology* / Q000378:metabolism; D003920:Diabetes Mellitus / Q000276:immunology / Q000503:physiopathology; D007108:Immune Tolerance; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D020799:Pancrelipase / Q000276:immunology*
chemical_list: D000941:Antigens; D015703:Antigens, CD; D000943:Antigens, Differentiation; D001426:Bacterial Proteins; D060908:CTLA-4 Antigen; D002352:Carrier Proteins; C556707:Ctla4 protein, mouse; C556708:Ctla4 protein, rat; C088933:Hel protein, Legionella pneumophila; D020799:Pancrelipase