LAUSR

Hubble’s law, established by famed astronomer Edwin Hubble, states that the universe is rapidly expanding. Although more figuratively, the same can be said of the rapidly expanding universe of CD4 T cells. In 1986, Mosmann and Coffman famously published a study postulating that all cytokine-secreting CD4 T helper (TH) cells could be characterized as either IFNγ-secreting Th1 cells, or IL-4-producing Th2 cells. With few exceptions, this theory was embraced for the better part of the next two decades. Fast forward to the early 2000’s, and it soon became clear that naïve TH cells could adopt additional cell fates in response to an array of cytokine signals that activate a variety of spatially and temporally regulated signaling pathways. For example, naïve TH cells recognizing antigen in the presence of TGF-β upregulate Foxp3 and differentiate into induced T regulatory (iTreg) cells that express IL-10 and suppress inflammatory responses. If these same naïve TH cells, however, sense TGF-β in the presence of other proinflammatory cytokines, such as IL-6, IL-1β, and/or IL-23, they upregulate RORγt expression, differentiate into Th17 cells that secrete IL-17A, IL-17F, and IL-22, and incite mucosal inflammation (reviewed in ref. ). The discovery of iTreg and Th17 cells spurred the descriptions of additional bona fide TH cell lineages over the past decade, including Th22 cells that secrete IL-22 in the absence of IL-17A/F, T follicular helper (TFH) cells—that express CXCR5, secrete IL-21 and regulate germinal center reactions—and Th9 cells, which differentiate from naïve TH cell precursors in the presence of TGF-β plus IL-4, and secrete the pro-inflammatory cytokine IL-9. Originally identified as a Th2 cytokine that promotes the proliferation of mast cells, erythroid precursors, and myeloid leukemia cells 6 IL-9 is now recognized for roles in antihelminthic and anti-tumor immunity, as well as allergic inflammation. In 2008, two studies independently demonstrated that TGF-β could subvert the canonical Th2 differentiation program and promote the development of effector TH cells that express IL-9 and IL-10 in the absence of other lineage-defining cytokines. 8 Since these initial reports, IL-9-expressing Th9 cells have become increasingly recognized for their unique pro-inflammatory functions, particularly at mucosal surfaces such as the gut and lung, and found to contribute to the pathogenesis of severe asthma and inflammatory bowel diseases (IBDs; i.e., Crohn’s disease and ulcerative colitis) in both mouse and man. Despite their recognized significance in mucosal inflammatory responses, important questions have lingered with respect to the signal transduction pathways and transcription factors that specify Th9 cell lineage commitment. A number of cytokine (e.g., IL-1β, IL-25, IL-33, TSLP) and co-stimulatory (OX-40, GITR) receptors have been shown to amplify Th9 cell differentiation. A large transcriptional network involving the canonical Th2-promoting transcription factors, GATA-3 and STAT6, the ETS family transcription factor, PU.1, interferon regulatory factor-4 (IRF4), and the AP1-associated transcription factor basic leucine zipper ATF-like transcription factor (BATF), have been shown to bind to conserved regulatory elements at the Il9 locus, thereby stabilizing IL-9 expression and supporting Th9 cell differentiation. More recently, the TL1A-DR3 signaling axis has been implicated in T-cell derived IL-9 production, Th9 development, and mucosal immunity. TL1A is a member of the TNF superfamily encoded by the TNFSF15 locus and induced in a variety of innate and adaptive immune cells following bacterial exposure or FcγR activation; TL1A promotes pro-inflammatory signaling in immune cells via binding to its cognate receptor, death receptor 3 (DR3; encoded by TNFRSF25), and inducing p38 MAP kinase and NF-κB-mediated signaling pathways. Experimental analyses in mouse model systems have revealed that genetic or pharmacological neutralization of TLA1 activity ameliorates, whereas TL1A overexpression exacerbates, IBD phenotypes, leading to the concept that microbe-induced TL1A expression tunes host mucosal immunity and inflammation. Consistent with this, TLA1 expression is upregulated in inflamed mucosal biopsies from IBD patients, and the presence of specific TL1A haplotypes is associated with both risk and disease severity in human IBDs. In 2015, Richard et al. described that TL1Adependent DR3 signaling intrinsically drives Th9 differentiation and Th9-mediated mucosal pathologies in vivo. This was followed by Thomas et al. who revealed that TL1A induces IL-9 production in human CD4 Th17 cells, and that IL-9 expression contributes to TLA1-driven IL-22 secretion in memory CD4 T cells. While these studies provided an intriguing link between TLA1 and Th9 cells in mucosal pathologies, the synchronized interaction of cytokines, lineage-specifying transcription factors, and transcriptional regulatory mechanisms downstream of TL1A signaling in Th9 cells has remained incompletely understood. In this issue of Mucosal Immunology, Michelsen and colleagues have extended their previous observations by identifying an intriguing new mechanism whereby TL1A acts synergistically with TGF-β1 and IL-4 to augment Th9 vigor through the BATF-related transcription factor, BATF3. The authors show that TL1A in the presence of the Th9 inducing cytokines, TGF-β and IL-4, increased IL-9 expression in both mouse and human TH cells. RNA-seq analyses of Th9 cells stimulated with TL1A (referred to as Th9-TL1A cells) revealed elevated expression of both BATF and BATF3