RESUMEN
Peptide-MHC class II complexes (pMHC II) are degraded by MARCH-I-mediated ubiquitination, and the stabilization of pMHC II by loss of its ubiquitination is one phenotype defining the activation of conventional dendritic cells (cDCs). However, the role of such stabilization of pMHC II in the context of T-cell activation/differentiation remains unclear. Here, we show that loss of pMHC II ubiquitination inhibits the activation and differentiation of CD4 T cells, probably through down-regulation of CD18/integrin ß2 and their diminished IL-12 production in a cell intrinsic manner. The cDCs generated from mice whose pMHC II ubiquitination is inhibited had a decreased ability to activate naive CD4 T cells and induce Th1/Th17 differentiation. In addition, cDCs whose MHC II ubiquitination was inhibited showed down-regulation of CD18/integrin beta 2 and of IL-12 production. This unexpected finding suggests that loss of MHC II ubiquitination contributes to the negative feedback of CD4 T-cell immune responses.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Diferenciación Celular/inmunología , Antígenos de Histocompatibilidad Clase II/inmunología , Ubiquitinación/inmunología , Animales , Presentación de Antígeno/genética , Presentación de Antígeno/inmunología , Antígeno B7-2/genética , Antígeno B7-2/inmunología , Antígeno B7-2/metabolismo , Antígenos CD18/inmunología , Antígenos CD18/metabolismo , Linfocitos T CD4-Positivos/metabolismo , Diferenciación Celular/genética , Células Cultivadas , Técnicas de Cocultivo , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Regulación hacia Abajo/inmunología , Citometría de Flujo , Antígenos de Histocompatibilidad Clase II/genética , Antígenos de Histocompatibilidad Clase II/metabolismo , Interleucina-12/inmunología , Interleucina-12/metabolismo , Activación de Linfocitos/genética , Activación de Linfocitos/inmunología , Ratones Noqueados , Ratones Transgénicos , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/inmunología , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitinación/genéticaRESUMEN
Heat shock protein 90 (HSP90) is a molecular chaperone required for efficient antigen presentation and cross-presentation. In addition, HSP90 was recently reported to interact with and stabilize the activation-induced cytidine deaminase (AID) and plays a critical role in immunoglobulin gene hypermutation and class switch recombination. In mice and humans, there are two HSP90 isoforms, HSP90α and HSP90ß, but the in vivo role of each isoform remains largely unknown. Here we have analyzed humoral immune responses in HSP90α-deficient mice. We found that HSP90α deficiency did not affect AID protein expression. B cell development and maturation, as well as immunoglobulin gene hypermuation and class switch, occurred normally in HSP90α-deficient mice. However, antibody production to a T-dependent antigen was elevated in the mutant mice and this was associated with enhanced MHC class II antigen presentation to T helper cells by dendritic cells. Our results reveal a previously unidentified inhibitory role for HSP90α isoform in MHC class II antigen presentation and the humoral immune response. Along with our recent finding that HSP90α is required for antigen cross-presentation, these results suggest that HSP90α controls the balance of humoral and cellular immunity by dictating the fate of presentation of exogenous antigen.
