Anergy in peripheral memory CD4(+) T cells induced by low avidity engagement of T cell receptor.
Induction of tolerance in self-reactive memory T cells is an important process in the prevention of autoimmune responses against peripheral self-antigens in autoimmune diseases. Although naive T cells can readily be tolerized, memory T cells are less susceptible to tolerance induction. Recently, we demonstrated that low avidity engagement of T cell receptor (TCR) by low densities of agonist peptides induced anergy in T cell clones. Since memory T cells are more responsive to lower antigenic stimulation, we hypothesized that a low avidity TCR engagement may induce tolerance in memory T cells. We have explored two antigenic systems in two transgenic mouse models, and have tracked specific T cells that are primed and show memory phenotype. We demonstrate that memory CD4(+) T cells can be rendered anergic by presentation of low densities of agonist peptide-major histocompatibility complex complexes in vivo. We rule out other commonly accepted mechanisms for induction of T cell tolerance in vivo, such as deletion, ignorance, or immunosuppression. Anergy is the most likely mechanism because addition of interleukin 2-reversed anergy in specific T cells. Moreover, cytotoxic T lymphocyte antigen (CTLA)-4 plays a critical role in the induction of anergy because we observed that there was increased surface expression of CTLA-4 on anergized T cells, and that injection of anti-CTLA-4 blocking antibody restored anergy in vivo.
Mirshahidi
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Department of Pathology, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA.
Huang
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Sadegh-Nasseri
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D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D060908:CTLA-4 Antigen; D017635:Clonal Anergy / Q000276:immunology*; D017637:Clonal Deletion; D015798:HLA-DR1 Antigen / Q000235:genetics / Q000276:immunology; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D006389:Hemagglutinins, Viral / Q000276:immunology; D018796:Immunoconjugates; D007156:Immunologic Memory / Q000276:immunology*; D016130:Immunophenotyping; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000276:immunology; D010455:Peptides / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D014373:Tuberculin / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D015798:HLA-DR1 Antigen; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D006389:Hemagglutinins, Viral; D018796:Immunoconjugates; D010446:Peptide Fragments; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D014373:Tuberculin; C086595:influenza hemagglutinin (306-318); D000069594:Abatacept