RESUMO
Expression of peripheral antigens in the thymus has been implicated in T cell tolerance and autoimmunity. Here we identified medullary thymic epithelial cells as being a unique cell type that expresses a diverse range of tissue-specific antigens. We found that this promiscuous gene expression was a cell-autonomous property of medullary epithelial cells and was maintained during the entire period of thymic T cell output. It may facilitate tolerance induction to self-antigens that would otherwise be temporally or spatially secluded from the immune system. However, the array of promiscuously expressed self-antigens appeared random rather than selected and was not confined to secluded self-antigens.
Assuntos
Autoantígenos/biossíntese , Regulação da Expressão Gênica , Tolerância a Antígenos Próprios/genética , Subpopulações de Linfócitos T/imunologia , Timo/metabolismo , Animais , Autoantígenos/genética , Autoantígenos/imunologia , Transplante de Medula Óssea , Células Cultivadas/metabolismo , DNA Complementar/genética , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/fisiologia , Células Epiteliais/metabolismo , Perfilação da Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Transgênicos , Especificidade de Órgãos , Quimera por Radiação , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Componente Amiloide P Sérico/biossíntese , Componente Amiloide P Sérico/deficiência , Componente Amiloide P Sérico/genética , Organismos Livres de Patógenos Específicos , Baço/citologia , Baço/metabolismo , Células Estromais/metabolismo , Testículo/citologia , Testículo/metabolismo , Timo/citologia , Timo/embriologia , Timo/transplante , Fatores de Transcrição/metabolismoRESUMO
A central tenet of T cell development postulates that if a developing thymocyte encounters self-antigen, it is induced to die via apoptosis, thereby protecting the organism from autoreactive T cells. We created transgenic mice that expressed a peptide antigen in the cortical epithelial cells of the thymus. This did not, however, result in deletion of specific T cells. Instead, antigen presentation by epithelial cells caused T cell receptor (TCR) internalization and increased gene rearrangement at the endogenous TCR alpha locus, or receptor editing. This editing mechanism in immature T cells parallels that which occurs in immature B cells, and has important implications for understanding positive and negative selection signaling in the thymus, and the limits of self-tolerance.