A Decade of Th9 Cells: Role of Th9 Cells in Inflammatory Bowel Disease

Abstract

T helper cell subsets play a critical role in providing protection against offending pathogens by secreting specific cytokines. However, unrestrained T helper cell responses can promote chronic inflammation-mediated inflammatory diseases. Dysregulated T helper cell responses have been suggested to be involved in the pathogenesis of multiple inflammatory diseases, including allergic airway inflammation, rheumatoid arthritis, and inflammatory bowel disease (IBD) among others. Aberrant pro-inflammatory responses induced by Th1, Th2, and Th17 subsets are known to trigger IBD. IBD is a chronic inflammatory disease characterized by weight loss, diarrhea, pain, fever, and rectal bleeding. It poses a major health burden worldwide owing to the increased risk of colorectal cancer development. Despite numerous therapeutic advancements, IBD still remains a major health burden due to the inefficiency of the conventional therapies. Recently, IL-9-secreting Th9 cells are known to be involved in the pathogenesis of IBD. However, the role of Th9 cells and their secretory cytokine IL-9 in IBD is unclear. The functional relevance of Th9 cells is also relatively understudied in IBD. Thus, investigating the actual role of various T helper cell subsets including Th9 cells in IBD is essential to develop novel therapies to treat IBD. Here, we highlight the role of Th9 cells in promoting IBD. We discuss the mechanisms that might be employed by Th9 cells and IL-9 in promoting IBD and thereby propose potential targets for the treatment of Th9 cell-mediated IBD.

Keywords: IL-9; T helper cells; Th9 cells; claudin; cytokines; inflammatory bowel disease; occludin; ulcerative colitis.

Figure 1

Complex role of IL-9-secreting Th9 cells in inflammatory bowel disease (IBD). Interleukin-9, a pleiotropic cytokine, is known to play dichotomous role in IBD. IL-9 secretion by Th9 cells disrupts intestinal barrier permeability resulting in the entry of innocuous antigens into the gut mucosa. This leads to antigen presentation by the dendritic cells to naïve CD4⁺ T cells culminating in T helper differentiation. Several cytokines are known to promote Th9 cell differentiation. IL-33 and IL-36 play a key role in Th9 cell proliferation in the gut mucosa culminating in aggravated colitis. IL-9 secreted by Th9 cells is also known to promote Th2-like responses culminating in the progression of ulcerative colitis (UC). However, IL-9 secreted by cells other than Th9 cells such as invariant natural killer T (iNKT) cells are known to dampen inflammatory responses rather than promoting them. Thus, anti-IL-9 antibody might not be the “magic bullet” to treat IBD. Instead, targeting the cytokines involved in Th9 cell expansion in the gut mucosa could be a possible strategy to maintain optimal Th9 cell development in the gut and thereby restrain Th9 cell-mediated UC.