Interleukin 9 (IL-9)-producing helper T (Th9) cells are essential for inducing anti-tumor immunity and inflammation in allergic and autoimmune diseases. Although transcription factors that are essential for Th9 cell differentiation have been identified, other signaling pathways that are required for their generation and functions are yet to be explored. Here, we identify that Epidermal Growth Factor Receptor (EGFR) is essential for IL-9 induction in helper T (Th) cells. Moreover, amphiregulin (Areg), an EGFR ligand, is critical for the amplification of Th9 cells induced by TGF-β1 and IL-4. Furthermore, our data show that Areg-EGFR signaling induces HIF1α, which binds and transactivates IL-9 and NOS2 promoters in Th9 cells. Loss of EGFR or HIF1α abrogates Th9 cell differentiation and suppresses their anti-tumor functions. Moreover, in line with its reliance on HIF1α expression, metabolomics profiling of Th9 cells revealed that Succinate, a TCA cycle metabolite, promotes Th9 cell differentiation and Th9 cell-mediated tumor regression.

Naïve CD4+ T cell differentiate into effector and regulatory subsets of helper T (Th) cells in various pathophysiological conditions and modulate tissue inflammation in autoimmune diseases. While cytokines play a key role in determining the fate of Th cells differentiation, metabolites, and metabolic pathways profoundly influence Th cells fate and their functions. Emerging literature suggests that interplay between metabolic pathways and cytokines potentiates T cell differentiation and functions in tissue inflammation in autoimmune diseases. Metabolic pathways, which are essential for the differentiation and functions of Th cell subsets, are regulated by cytokines, nutrients, growth factors, local oxygen levels, co-activation receptors, and metabolites. Dysregulation of metabolic pathways not only alters metabolic regulators in Th cells but also affect the outcome of tissue inflammation in autoimmune and allergic diseases. Understanding the modulation of metabolic pathways during T cells differentiation may potentially lead to a therapeutic strategy for immune-modulation of autoimmune and allergic diseases. In this review, we summarize the role of metabolic checkpoints and their crosstalk with different master transcription factors and signaling molecules in differentiation and function of Th subsets, which may potentially unravel novel therapeutic interventions for tissue inflammation and autoimmune disorders.

Interleukin 9 (IL-9)-producing helper T (Th9) cells have a crucial effector function in inducing allergic inflammation, autoimmunity, immunity to extracellular pathogens and anti-tumor immune responses. Although the cytokines that lead to the differentiation of human Th9 cells have been identified, other factors that support the differentiation of Th9 cells have not been identified yet. Here we show that the extracellular ATP (eATP) induces the differentiation of Th9 cells. We further show that eATP induces the production of nitric oxide (NO), which create a feed forward loop in the differentiation of human Th9 cells, as inhibition of purinergic receptor signaling suppressed the generation of human Th9 cells while exogenous NO could rescue generation of Th9 cells even upon inhibition of purinergic receptor signaling. Moreover, we show that ATP promotes mTOR and HIF1α dependent generation of Th9 cells. Our findings thus identify that ATP induced nitric oxide potentiate HIF1α-mediated metabolic pathway that leads to IL-9 induction in Th9 cells. Here we identified that the ATP-NO-mTOR-HIF1α axis is essential for the generation of human Th9 cells and modulation of this axis may lead to therapeutic intervention of Th9-associated disease conditions.

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