T-cell tolerance and autoimmunity to systemic and tissue-restricted self-antigens.
We have used transgenic mouse models to examine the mechanisms of tolerance in CD4(+) T lymphocytes to soluble, systemic and cell-associated, tissue-restricted self-antigens. Anergy to an islet antigen, as a model of a tissue antigen, is dependent on the inhibitory receptor cytotoxic T-lymphocyte antigen-4 (CTLA-4), and tissue-restricted autoimmunity is inhibited by regulatory T lymphocytes. Anergy to a circulating systemic antigen can occur independently of CTLA-4 signals, and it is induced primarily by a block in proximal receptor-initiated signals. CD4(+)CD25(+) regulatory T cells are generated in response to both forms of self-antigens, but the induction is much more efficient with the tissue antigen. Receptor desensitization can be induced by the systemic antigen even in the absence of regulatory T cells, but tolerance can be broken by immunization much more easily if these cells are absent. Deletion of mature T cells is striking with the systemic antigen; there is little evidence to support peripheral deletion as a mechanism of tolerance to the tissue antigen. Thus, both distinct and overlapping mechanisms account for unresponsiveness to different forms of self-antigens. These results establish a foundation for searching for genetic influences and pathogenic mechanisms in organ-specific and systemic autoimmune diseases.
Lohr
Jens
J
Department of Pathology, University of California San Francisco School of Medicine, San Francisco, CA 94143, USA.
Knoechel
Birgit
B
Nagabhushanam
Vijaya
V
Abbas
Abul K
AK
D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D001324:Autoantigens / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology*; D060908:CTLA-4 Antigen; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics / Q000276:immunology*; D009928:Organ Specificity; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
D015703:Antigens, CD; D000943:Antigens, Differentiation; D001324:Autoantigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse