Th9 cell development requires a BATF-regulated transcriptional network

Abstract

T helper 9 (Th9) cells are specialized for the production of IL-9, promote allergic inflammation in mice, and are associated with allergic disease in humans. It has not been determined whether Th9 cells express a characteristic transcriptional signature. In this study, we performed microarray analysis to identify genes enriched in Th9 cells compared with other Th subsets. This analysis defined a transcriptional regulatory network required for the expression of a subset of Th9-enriched genes. The activator protein 1 (AP1) family transcription factor BATF (B cell, activating transcription factor-like) was among the genes enriched in Th9 cells and was required for the expression of IL-9 and other Th9-associated genes in both human and mouse T cells. The expression of BATF was increased in Th9 cultures derived from atopic infants compared with Th9 cultures from control infants. T cells deficient in BATF expression had a diminished capacity to promote allergic inflammation compared with wild-type controls. Moreover, mouse Th9 cells ectopically expressing BATF were more efficient at promoting allergic inflammation than control transduced cells. These data indicate that BATF is a central regulator of the Th9 phenotype and contributes to the development of allergic inflammation.

Human Vδ2 T cells are a major source of interleukin-9

“…Furthermore, we found IL-9 production in Vδ2 T cells accompanied by elevated levels of CXCL13 and TNFSF13B (BAFF). CD4 Th9 cells can coexpress TNFSF13B (38), and CXCL13 can be induced in response to TGF-β (39). Both mediators might be relevant for the interaction with B cells.…”

IL-9 Expression by Invariant NKT Cells Is Not Imprinted during Thymic Development

“…Transcriptional regulation of Th9 differentiation in conventional CD4 T cells is complex, as it relies on several transcription factors, including PU.1, GATA-3, BATF, and IFN regulatory factor (IRF)-4 (31,(33)(34)(35). To identify the controlling factors of IL-9 gene expression in iNKT cells, we first defined the kinetics of IL-9 expression at protein and mRNA levels to determine the best time point for analysis.…”

Les lymphocytes Th9

“…En l'absence de STAT5, les lymphocytes T sont donc incapables de sécréter de l'IL-9 [4]. STAT5 induit également l'expression d'IRF4 (interferon regulatory factor 4) et de Spi-1/PU.1, deux facteurs de transcription qui sont nécessaires à la différenciation des lymphocytes en Th9 [5][6][7] (Figure 1). STAT6 est un autre facteur de transcription essentiel qui est activé après stimulation par le récepteur de l'IL-4 porté par les lymphocytes.…”

“…STAT6 est un autre facteur de transcription essentiel qui est activé après stimulation par le récepteur de l'IL-4 porté par les lymphocytes. STAT6 peut se fixer directement au promoteur de l'Il9 [8,9], mais il est également capable d'induire l'expression des facteurs de transcription IRF4 et BATF (basic leucine zipper transcription factor, ATF-like) qui, bien que non spé-cifiques du sous-type Th9, sont essentiels à la différenciation de ces cellules [5]. IRF4 est crucial pour la différenciation Th9.…”

“…IRF4 est crucial pour la différenciation Th9. Il se lie directement au promoteur de l'Il9 [5,6] et, tout comme STAT6, est capable de bloquer l'expression de facteurs de transcription répresseurs de la différenciation Th9 comme Tbet (T-box expressed in T cells) ou FOXP3 (forkhead box P3), qui contôlent, eux, la maturation des cellules vers d'autres sous-populations lymphocytaires [5]. Le facteur de transcription GATA-3 (GATA binding protein 3) est, quant à lui, fortement induit dans les cellules de type Th2 à la suite de la fixation de l'IL-4 sur son récepteur IL-4Ra.…”