RESUMEN
The lymphokine interleukin-2 (IL-2) is responsible for autocrine cell cycle progression and regulation of immune responses. Uncontrolled secretion of IL-2 results in adverse reactions ranging from anergy, to aberrant T cell activation, to autoimmunity. With the use of fluorescent in situ hybridization and single-cell polymerase chain reaction in cells with different IL-2 alleles, IL-2 expression in mature thymocytes and T cells was found to be tightly controlled by monoallelic expression. Because IL-2 is encoded at a nonimprinted autosomal locus, this result represents an unusual regulatory mode for controlling the precise expression of a single gene.
Asunto(s)
Alelos , Linfocitos T CD4-Positivos/inmunología , Regulación de la Expresión Génica , Interleucina-2/genética , Animales , Linfocitos T CD4-Positivos/citología , Concanavalina A/farmacología , Replicación del ADN , Femenino , Citometría de Flujo , Heterocigoto , Hibridación Fluorescente in Situ , Interleucina-2/biosíntesis , Activación de Linfocitos , Masculino , Ratones , Ratones Endogámicos C57BL , Muridae , Mutación , Reacción en Cadena de la Polimerasa , Fase S , Transcripción GenéticaRESUMEN
T cell development is tightly controlled by thymic stromal cells. Alterations in stromal architecture affect T cell maturation and the development of self-tolerance. The monogenic autoimmune syndrome APECED (autoimmune-polyendocrinopathy-candidiasis-ectodermal dystrophy) is characterized by the loss of self-tolerance to multiple organs. Although mutations in the autoimmune regulator (AIRE) gene are responsible for this disease, the function of AIRE is not known. Here we report on the spatial and temporal pattern of murine Aire expression during thymic ontogeny and T cell selection. Early during development, thymic Aire transcription is critically dependent on RelB and occurs in epithelial cells in response to lymphocyte-mediated signals. In adult tissue, Aire expression is confined to the medulla and the corticomedullary junction, where it is modulated by thymocytes undergoing negative selection. Aire may determine thymic stromal organization and with it the induction of self-tolerance.