Induction or protection from experimental autoimmune encephalomyelitis depends on the cytokine secretion profile of TCR peptide-specific regulatory CD4 T cells.
Autoimmune diseases can result from the breakdown of regulation and subsequent activation of self-antigenic determinant-reactive T cells. During the evolution of the autoimmune response to myelin basic protein (MBP) in B10.PL mice, several distinct T cell populations expand: the effectors mediating experimental autoimmune encephalomyelitis (EAE) are MBP-reactive, CD4+, and predominantly TCR Vbeta8.2+; in addition, at least two regulatory populations can be detected--one comprised of Vbeta14+ CD4 T cells, reactive to a framework region 3 determinant on the Vbeta8.2 chain, and a second that is CD8+ and reactive to another Vbeta8.2 determinant. The combined action of these two regulatory cell types controls disease-causing effectors, resulting in spontaneous recovery from disease. In this report, we reveal that the cytokine secretion pattern of TCR peptide-specific regulatory CD4 T cells can profoundly influence whether a type 1 or type 2 population predominates among MBP-specific CD4 effectors. The priming of type 1 regulatory T cells results in deviation of the Ag-specific effector T cell population in a type 2 direction and protection from disease. In contrast, induction of type 2 regulatory T cells results in exacerbation of EAE, poor recovery, and an increased frequency of type 1 effectors. Thus, the encephalitogenic potential of the MBP-reactive effector population is crucially and dominantly influenced by the cytokine secretion phenotype of regulatory CD4 T cells. These findings have important implications in understanding peripheral tolerance to self-Ags as well as in the design of TCR-based therapeutic approaches.
Kumar
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V
Department of Microbiology and Molecular Genetics, University of California, Los Angeles 90095, USA. Vipink@liai.org
Sercarz
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E
D000281:Administration, Intranasal; D000818:Animals; D001324:Autoantigens / Q000008:administration & dosage / Q000276:immunology*; D001327:Autoimmune Diseases / Q000209:etiology / Q000276:immunology* / Q000517:prevention & control; D015551:Autoimmunity; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000209:etiology / Q000276:immunology* / Q000517:prevention & control; D005260:Female; D007114:Immunization; D008213:Lymphocyte Activation; D008222:Lymphokines / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D004676:Myelin Basic Protein / Q000008:administration & dosage / Q000276:immunology*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology*; D013047:Specific Pathogen-Free Organisms; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism*; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism*
D001324:Autoantigens; D008222:Lymphokines; D004676:Myelin Basic Protein; D010446:Peptide Fragments; D016693:Receptors, Antigen, T-Cell, alpha-beta