RESUMO
The molecular basis of CD28-dependent costimulation of T cells is poorly understood. Bcl-xgamma is a member of the Bcl-x family whose expression is restricted to activated T cells and requires CD28-dependent ligation for full expression. We report that Bcl-xgamma-deficient (Bcl-xgamma-/-) T cells display defective proliferative and cytokine responses to CD28-dependent costimulatory signals, impaired memory responses to proteolipid protein peptide (PLP), and do not develop PLP-induced experimental autoimmune encephalomyelitis (EAE). In contrast, enforced expression of Bcl-xgamma largely replaces the requirement for B7-dependent ligation of CD28. These findings identify the Bcl-xgamma cytosolic protein as an essential downstream link in the CD28-dependent signaling pathway that underlies T cell costimulation.
Assuntos
Antígenos CD28/metabolismo , Regulação da Expressão Gênica/imunologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Linfócitos T/metabolismo , Transferência Adotiva , Animais , Apoptose/imunologia , Autoimunidade/imunologia , Complexo CD3/metabolismo , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/imunologia , Divisão Celular/efeitos dos fármacos , Divisão Celular/imunologia , Células Cultivadas , Quimera , Encefalomielite Autoimune Experimental/imunologia , Marcação de Genes , Interleucina-2/farmacologia , Camundongos , Camundongos Endogâmicos , Camundongos Transgênicos , Isoformas de Proteínas/deficiência , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/deficiência , Proteínas Proto-Oncogênicas c-bcl-2/genética , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Proteína bcl-XRESUMO
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.
