RESUMEN
Regulatory T (Treg) cells maintain immunological tolerance in steady-state and after immune challenge. Activated Treg cells can undergo further differentiation into an effector state that highly express genes critical for Treg cell function, including ICOS, TIGIT and IL-10, although how this process is controlled is poorly understood. Effector Treg cells also specifically express the transcriptional regulator Blimp-1 whose expression overlaps with many of the canonical markers associated with effector Treg cells, although not all ICOS+TIGIT+ Treg cells express Blimp-1 or IL-10. In this study, we addressed the role of Blimp-1 in effector Treg cell function. Mice lacking Blimp-1 specifically in Treg cells mature normally, but succumb to a multi-organ inflammatory disease later in life. Blimp-1 is not required for Treg cell differentiation, with mutant mice having increased numbers of effector Treg cells, but regulated a suite of genes involved in cell signaling, communication and survival, as well as being essential for the expression of the immune modulatory cytokine IL-10. Thus, Blimp-1 is a marker of effector Treg cells in all contexts examined and is required for the full functionality of these cells during aging.
Asunto(s)
Envejecimiento/inmunología , Inflamación/inmunología , Factor 1 de Unión al Dominio 1 de Regulación Positiva/metabolismo , Linfocitos T Reguladores/inmunología , Animales , Diferenciación Celular , Células Cultivadas , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Tolerancia Inmunológica , Inflamación/genética , Interleucina-10/genética , Interleucina-10/metabolismo , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Factor 1 de Unión al Dominio 1 de Regulación Positiva/genética , Transducción de SeñalRESUMEN
The transcriptional repressor/activator interferon regulatory factor 8 (IRF8) modulates the differentiation of a multitude of hematopoietic lineages. However, the role of IRF8 in CD4(+) T-cell development is less well defined, with a recent study implicating IRF8 as an intrinsic repressor of interleukin-17 (IL-17) expressing T helper type 17 (Th17) cell differentiation. Using an IRF8-EGFP reporter strain we have confirmed that IRF8 is expressed in all T helper lineages, including Th17 cells. The loss of IRF8 did not affect Th17 differentiation in vitro, beyond a small increase in IL-22 expression. Moreover, IRF8 deficiency did not enhance the Th17 immune response in experimental T-cell transfer colitis. Together, these results suggest that IRF8 does not play an essential intrinsic role in Th17 cell differentiation.
