The ETS Family Transcription Factors Etv5 and PU.1 Function in Parallel To Promote Th9 Cell Development

Abstract

The IL-9-secreting Th9 subset of CD4 T helper cells develop in response to an environment containing IL-4 and TGFβ, promoting allergic disease, autoimmunity, and resistance to pathogens. We previously identified a requirement for the ETS family transcription factor PU.1 in Th9 development. In this report we demonstrate that the ETS transcription factor ETV5 promotes IL-9 production in Th9 cells by binding and recruiting histone acetyltransferases to the Il9 locus at sites distinct from PU.1. In cells that are deficient in both PU.1 and ETV5 there is lower IL-9 production than in cells lacking either factor alone. In vivo loss of PU.1 and ETV5 in T cells results in distinct affects on allergic inflammation in the lung, suggesting that these factors function in parallel. Together, these data define a role for ETV5 in Th9 development and extend the paradigm of related transcription factors having complementary functions during differentiation.

The transcription factor network in Th9 cells

“…IL-9 production was decreased in the absence of ETV5, and ectopic expression of ETV5 increased IL-9 production [56]. ETV5, which also promotes IL-17A/F production in Th17 cells [57], significantly bound to the Il9 gene at regions distinct from the promoter that bound PU.1 [56](Fig. 2).…”

“…2). Binding of the HAT p300 was dependent on ETV5, but Gcn5 binding was normal in the absence of ETV5 [56]. Th9 cells that were doubly deficient in PU.1 and ETV5 had less IL-9 production than Th9 cells from either single deficient strain.…”

“…Th9 cells that were doubly deficient in PU.1 and ETV5 had less IL-9 production than Th9 cells from either single deficient strain. Interestingly, the effects on repression of IL-4 were not cumulative in double-deficient T cells [56]. In vivo, PU.1 and ETV5 seemed to have significant effects on some overlapping but also some distinct parameters of allergic inflammation.…”

IL-9 and Th9 cells in health and diseases—From tolerance to immunopathology

“…For example, those that can engage the Il9 promoter region include PU.1, IRF1, IRF4, STAT5, STAT6, NFAT, GATA1, GATA3, Smads, Etv5 and Notch, as well as NF-κB, BATF, AP-1[9]. Etv5 can also bind the CNS0 and CNS2 regions and mediate chromatin remodeling by recruiting the histone acetyltransferase p300 [53]. TCR stimulation, polarizing cytokines, and costimulatory molecules, especially those in the TNFR superfamily, are all involved in the expression of such transcription factors.…”

Epigenetic Alterations in Cellular Immunity: New Insights into Autoimmune Diseases

“…A recent study identified a demand of ETS transcription factor ETS variant 5 (ETV5) to augment IL-9+ Th9 cells with an enrichment of histone acetyltransferases (HATs) within the IL-9 gene promoter. In vitro study showed that a reduction of p300 in the absence of ETV5, accompanied by low level of histone H3 acetylation and H4K16 acetylation enriched in the Il9 promoter [63]. …”