The involvement of T cell receptor peptide-specific regulatory CD4+ T cells in recovery from antigen-induced autoimmune disease.
Experimental allergic encephalomyelitis (EAE) is a prototype for CD4+ T cell-mediated autoimmune diseases. Immunization with myelin basic protein (MBP) in B10.PL mice results in EAE, and a majority of animals recover permanently from the disease. Most MBP-reactive encephalitogenic T cells recognize an immunodominant NH2-terminal peptide, Ac1-9, and predominantly use the T cell receptor (TCR) V beta 8.2 gene segment. Here we report that in mice recovering from MBP-induced EAE, peripheral T cells proliferate in response to a single immunodominant TCR peptide from the V beta 8.2 chain (amino acids 76-101), indicating natural priming during the course of the disease. Cloned T cells, specific for this TCR peptide, specifically downregulate proliferative responses to Ac1-9 in vivo and also protect mice from MBP-induced EAE. These regulatory T cells express CD4 molecules and recognize a dominant peptide from the TCR variable framework region of V beta 8.2, in the context of the major histocompatibility complex class II molecule, I-Au, and predominantly use the TCR V beta 14 gene segment. This is the first demonstration of the physiological induction of TCR peptide-specific CD4+ T cells that result from MBP immunization and that are revealed only during the recovery from disease. The downregulation of disease-causing T cells by TCR peptide-specific T cells offers a mechanism for antigen-specific, network-induced recovery from autoimmune disease.
Kumar
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Department of Microbiology and Molecular Genetics, University of California, Los Angeles 90024.
Sercarz
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D000595:Amino Acid Sequence; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; D007116:Immunization, Passive; D008213:Lymphocyte Activation; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D004676:Myelin Basic Protein / Q000276:immunology; D010455:Peptides / Q000737:chemistry / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry / Q000276:immunology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology*
D004676:Myelin Basic Protein; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D016693:Receptors, Antigen, T-Cell, alpha-beta