RESUMEN
MHC/self peptide interactions with cognate coreceptor/TCR complexes are central to homeostasis of the T cell repertoire. Recent reports have also underlined the critical role of IL-15/IL-2 cytokines in regulating this homeostatic process. In this study, we investigate mechanisms that regulate potentially autoreactive CD8 cells that have escaped intrathymic selection. These cells, upon exit from the thymus, express high levels of CD44, B220, and the IL-15R/IL-2R, and undergo fas-dependent apoptosis. Defects in fas signaling allow increased IL-15/IL-2-dependent survival of these CD44/B220(+) CD8(+) as well as the double-negative T cells characteristic of lpr disease.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Supresión Clonal , Trastornos Linfoproliferativos/inmunología , Trastornos Linfoproliferativos/patología , Receptor fas/fisiología , Animales , Linfocitos T CD8-positivos/metabolismo , Ciclo Celular/genética , Ciclo Celular/inmunología , Muerte Celular/genética , Muerte Celular/inmunología , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Movimiento Celular/genética , Movimiento Celular/inmunología , Supresión Clonal/genética , Proteínas de Unión al ADN/metabolismo , Femenino , Antígenos H-2/metabolismo , Homeostasis/genética , Homeostasis/inmunología , Receptores de Hialuranos/biosíntesis , Antígenos Comunes de Leucocito/biosíntesis , Trastornos Linfoproliferativos/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos MRL lpr , Ratones Transgénicos , Fragmentos de Péptidos/metabolismo , Receptores de Interleucina-2/biosíntesis , Receptores de Interleucina-2/fisiología , Transducción de Señal/genética , Transducción de Señal/inmunología , Timo/inmunología , Timo/metabolismo , Timo/patología , Regulación hacia Arriba/genética , Regulación hacia Arriba/inmunología , Receptor fas/genéticaRESUMEN
Viral infections can trigger tissue destruction through innate and/or adaptive immune mechanisms. Here we show that these pathways can be differentially activated after infection by different strains of the herpes simplex virus-1 (HSV-1) virus. Infection of murine corneal tissue by HSV-1 (KOS) triggers an autoreactive clone of CD4 cells that is cross-reactive with an HSV-1 epitope to initiate corneal destruction. In contrast, ocular infection by the HSV-1 (RE) strain induces murine corneal destruction through direct, T cell-independent, activation of the innate immune system. Although the relative role of these two pathways to blindness following clinical HSV-1 ocular infection is unknown, this analysis suggests a general experimental approach to evaluate the relative contribution of adaptive and innate immune mechanisms to virally induced host tissue destruction.