RESUMEN
Invariant NKT (iNKT) cells differentiate in the thymus into three distinct lineages defined by their cytokine and transcription factor expression. Signaling lymphocyte activation molecule (SLAM)-associated protein (SAP) is essential for early stages of iNKT cell development, but its role during terminal differentiation of iNKT1, iNKT2, or iNKT17 cells remains unclear. Taking advantage of SAP-deficient mice expressing a Vα14-Jα18 TCRα transgene, we found that SAP is critical not only for IL-4 production but also for the terminal differentiation of IL-4-producing iNKT2 cells. Furthermore, without SAP, the IL-17 producing subset is expanded, while IFN-γ-producing iNKT1 differentiation is only moderately compromised. Lack of SAP reduced the expression of the transcription factors GATA-3 and promyelocytic leukemia zinc finger, but enhanced the levels of retinoic acid receptor-related orphan receptor γt. In the absence of SAP, lineage commitment was actually shifted toward the emergence of iNKT17 over iNKT2 cells. Collectively, our data unveil a new critical regulatory function for SAP in thymic iNKT cell fate decisions.
Asunto(s)
Diferenciación Celular/inmunología , Células T Asesinas Naturales/citología , Células T Asesinas Naturales/metabolismo , Proteína Asociada a la Molécula de Señalización de la Activación Linfocitaria/metabolismo , Subgrupos de Linfocitos T/citología , Subgrupos de Linfocitos T/metabolismo , Animales , Biomarcadores , Células Cultivadas , Inmunofenotipificación , Interleucina-17/biosíntesis , Interleucina-4/biosíntesis , Ratones , Ratones Noqueados , Ratones Transgénicos , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Fenotipo , Proteína Asociada a la Molécula de Señalización de la Activación Linfocitaria/deficiencia , Proteína Asociada a la Molécula de Señalización de la Activación Linfocitaria/genéticaAsunto(s)
Infecciones por Virus de Epstein-Barr/genética , Granuloma/genética , Proteína Asociada a la Molécula de Señalización de la Activación Linfocitaria/deficiencia , Proteína Asociada a la Molécula de Señalización de la Activación Linfocitaria/genética , Agammaglobulinemia/genética , Niño , Predisposición Genética a la Enfermedad/genética , Granuloma/virología , Humanos , Masculino , Mutación/genéticaRESUMEN
X-linked lymphoproliferative disease (XLP-1) is an often-fatal primary immunodeficiency associated with the exuberant expansion of activated CD8(+) T cells after Epstein-Barr virus (EBV) infection. XLP-1 is caused by defects in signaling lymphocytic activation molecule (SLAM)-associated protein (SAP), an adaptor protein that modulates T cell receptor (TCR)-induced signaling. SAP-deficient T cells exhibit impaired TCR restimulation-induced cell death (RICD) and diminished TCR-induced inhibition of diacylglycerol kinase α (DGKα), leading to increased diacylglycerol metabolism and decreased signaling through Ras and PKCθ (protein kinase Cθ). We show that down-regulation of DGKα activity in SAP-deficient T cells restores diacylglycerol signaling at the immune synapse and rescues RICD via induction of the proapoptotic proteins NUR77 and NOR1. Pharmacological inhibition of DGKα prevents the excessive CD8(+) T cell expansion and interferon-γ production that occur in SAP-deficient mice after lymphocytic choriomeningitis virus infection without impairing lytic activity. Collectively, these data highlight DGKα as a viable therapeutic target to reverse the life-threatening EBV-associated immunopathology that occurs in XLP-1 patients.