The development and in vivo function of T helper 9 cells

Abstract

The specialized cytokine secretion profiles of T helper (TH) cells are the basis for a focused and efficient immune response. On the twentieth anniversary of the first descriptions of the cytokine signals that promote the differentiation of interleukin-9 (IL-9)-secreting T cells, this Review focuses on the extracellular signals and the transcription factors that promote the development of what we now term TH9 cells, which are characterized by the production of this cytokine. We summarize our current understanding of the contribution of TH9 cells to both effective immunity and immunopathological disease, and we propose that TH9 cells could be targeted for the treatment of allergic and autoimmune disease.

Figure 1. The influence of cytokine environment on T_H cell differentiation

While the strength of TCR signaling and the quality of co-stimulation have been demonstrated to influence naïve CD4+ T cell polarization, the cytokine environment largely dictates T_H differentiation. The prototypical cytokines and their corresponding signaling pathways (STATs, Smads) regulating each T_H fate are depicted. Additional cytokine and signaling pathways influencing T_H differentiation exist but have effects on the development of multiple T_H subsets. For example, IL-2, through the STAT5 signaling pathway, is important during T_H1, T_H2, T_H9, and T_reg development but inhibits T_FH and T_H17 differentiation.

Figure 2. Cytokine and signal transduction pathways that promote IL-9 production and T_H9 differentiation

The differentiation of IL-9-secreting T cells requires IL-2/STAT5 and IL-4/STAT6 signaling and polarized from Th2 differentiation via TGF-β-derived signals. Although this combination of cytokines is sufficient for differentiation of T_H9 cells, a number of other signaling pathways have been identified that further enhance IL-9 production by these cells. Accessory cytokines act to induce NF-κB (IL-1, IL-25 and IL-33) or act through STAT1 to induce IRF1 expression (type I IFNs, IL-1β). TCR and co-stimulatory molecules also play an important role in Il9 transcription upon interaction with antigen presenting cells, largely by activation of NFAT (TCR, CD28-mediated co-stimulation) and NF-κB (TCR, 41BB and OX40 co-stimulation).

Figure 3. T_H9 cells in immunity and disease

Proposed effector activity of T_H9 cells in human disease. (I) Th9 cells, present in the draining lymph nodes and airways, are strongly linked in contributing to asthmatic disease. Th9-derived IL-9 can exacerbate the immune response by enhancing antibody production and increasing immune cell infiltration and activity within the respiratory tract. Furthermore, IL-9 can increase collagen deposition, induce smooth muscle hyperplasia, and alter respiratory epithelial cell function. (II) Th9 cells have been implicated in contributing to IBD particularly ulcerative colitis. Th9 cells, through IL-9 production, can impair tissue repair process, increase intestinal permeability, and may enhance inflammatory Th responses (III) Depending on the parasite, Th9 cells can exhibit potent anti-helminth activity through the production of IL-9. IL-9 mediates anti-parasitic activity by altering epithelial cell function, increasing immune cell infiltration into infected locations, and augmenting leukocyte immune function. (IV) Murine studies have strongly implicated Th9 cells in exhibiting anti-tumor activity, particularly in melanoma. Th9 cells, through IL-9 production, can increase lymphocyte infiltration into the tumor and enhance the anti-tumor activity of mast cells. Furthermore, Th9-derived IL-21 can limit tumor growth by stimulating lymphocyte anti-tumor activity, and Th9-derived IL-3 can promote DC survival, potentially enhancing the induction of anti-tumor adaptive immune responses. The location of T_H9 effector activity (draining lymphoid tissue and/or inflammatory site) has not been clearly determined.

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