title: Breaking T cell tolerance with foreign and self co-immunogens. A study of autoimmune B and T cell epitopes of cytochrome c.
abstract: The initiation of autoimmune B cell and T cell responses by self Ag or by foreign pathogens (molecular mimics) is not well understood. In the present study, cytochrome c (cyt c) was used as a model autoantigen to investigate how self-proteins are involved in the priming of autoimmune T cell responses. Immunization with foreign cyt c has been extensively analyzed in previous studies as a model for both humoral and cellular immune responses. Mice do not, however, make antibody or T cell responses to immunization with self (mouse) cyt c. In addition, T cell tolerance can be broken by autoreactive B cells that are readily elicited by immunization with cross-reactive foreign cyt c. These immune B cells presumably bind self cyt c and process and present the self Ag to stimulate an autoreactive T cell response. Autoreactive T cell clones derived by this mechanism are all specific for determinants within amino acids 1-80 of the cyt c protein presented by I-Ek. No T cell responses were observed to the carboxyl terminal 81-104 fragment that dominates the response to foreign cyt c. All clones derived in this study are stimulated by a polypeptide encompassing amino acids 54-68 and utilized the V beta 8.2 TCR gene. In contrast, T cells stimulated by foreign cyt c did indeed respond to fragment 81-104 and appear to utilize alternate TCR genes. Our data demonstrate that B cells specific for linear determinants distributed along the entire length of the foreign cyt c molecule can provide the stimulus required for breaking T cell tolerance to self cyt c. The applications of this work to understanding the mechanisms of autoimmune disease are discussed.
authors.affiliation: Department of Medicine, Yale University School of Medicine, New Haven, CT 06510.
authors.forename: M J
authors.initials: MJ
authors.lastname: Mamula
authors.forename: R H
authors.initials: RH
authors.lastname: Lin
authors.forename: C A
authors.initials: CA
authors.lastname: Janeway
authors.forename: J A
authors.initials: JA
authors.lastname: Hardin
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D015551:Autoimmunity / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D003429:Cross Reactions; D003574:Cytochrome c Group / Q000276:immunology*; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; D006801:Humans; D007108:Immune Tolerance; D008213:Lymphocyte Activation; D051379:Mice; D008815:Mice, Inbred Strains; D051381:Rats; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D016415:Sequence Alignment; D013045:Species Specificity; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D001324:Autoantigens; D003574:Cytochrome c Group; D016693:Receptors, Antigen, T-Cell, alpha-beta