TH9 cell differentiation, transcriptional control and function in inflammation, autoimmune diseases and cancer

Abstract

Naïve CD4+T cells differentiate into various T cell subsets depending on the specific cytokine environment. TH9 cells are less well-characterized than other T cell subsets, and factors that control their development and function have only recently been identified. It is now clear that TH9 cells play critical roles in immune-mediated diseases, including allergic airway, autoimmune and inflammatory bowel diseases, and cancer. Thus, the promotion or suppression of TH9 cell differentiation, transcriptional control and function may provide novel treatments for clinical inflammation, autoimmune diseases and tumors.

Keywords: T cell differentiation; TH9; allergic airway inflammation; autoimmune diseases; tumor.

Figure 1. Differentiation of T cell lineages

Naïve CD4⁺T cells are activated by T cell receptor (TCR) signaling and differentiate into various T cell lineages depending on the cytokine environment. Prototypical differentiation cytokine sets, corresponding specific transcriptional factors, and functional cytokine effects that regulate T_H cell fate and functions (including T_H9 cells) are shown.

Figure 2. Transcriptional control of T_H9 cell differentiation

IL-4, TGFβ1, IL-2, TCR, and other stimuli induce the expression of downstream transcriptional factors, including STAT6, IRF4, BATF, SMAD3, TAK1-SIRT1-mTOR-HIF1α, PU.1, STAT5, Bcl6, NF-kB, and NFAT, that interact with Il9 promoters to increase IL-9 expression and secretion.

Figure 3. T_H9 cells in immune-mediated diseases

T_H9 cells have potent protective or pathological roles in immune-mediated diseases, including allergic airway disease, inflammatory bowel diseases, autoimmune diseases (EAE, SLE), and pathogen infections.

Figure 4. T_H9 differentiation and function in anti-tumor immunity

T_H9 cells have anti-tumor activity, particularly in melanoma. A., iT_reg cells and other T cell subsets can differentiate into T_H9 cells, which affect anti-tumor immunity. T_H9 cells exert anti-tumor effects primarily via the secretion of the cytokines IL-9 B. and IL-21 C. IL-9 promotes tumor cell death directly by increasing granzyme B release and indirectly by increasing DC survival and recruitment, inducing host anti-tumor CD8⁺CTL response, or increasing Tc9 activity. IL-21 contributes to anti-tumor immunity by promoting NK cell cytolytic function and CD8⁺CTL response.