Effector T Helper Cell Subsets in Inflammatory Bowel Diseases

Abstract

The gastrointestinal tract is a site of high immune challenge, as it must maintain a delicate balance between tolerating luminal contents and generating an immune response toward pathogens. CD4⁺ T cells are key in mediating the host protective and homeostatic responses. Yet, CD4⁺ T cells are also known to be the main drivers of inflammatory bowel disease (IBD) when this balance is perturbed. Many subsets of CD4⁺ T cells have been identified as players in perpetuating chronic intestinal inflammation. Over the last few decades, understanding of how each subset of Th cells plays a role has dramatically increased. Simultaneously, this has allowed development of therapeutic innovation targeting specific molecules rather than broad immunosuppressive agents. Here, we review the emerging evidence of how each subset functions in promoting and sustaining the chronic inflammation that characterizes IBD.

Keywords: Crohn’s disease; T helper cells; inflammatory bowel disease; inflammatory cytokines; transcription factors; ulcerative colitis.

Figure 1

Critical factors in the differentiation of effector Th cells during inflammatory bowel disease (IBD). T helper cells recognize antigen presented in the context of major histocompatibility complex II on antigen-presenting cells in a T cell receptor-dependent fashion (not shown). In conjunction with assorted co-stimulatory signals (i.e., CD80/86–CD28 interaction and others), these signals initiate a program of cell division and differentiation. This differentiation program can be profoundly influenced based on the cytokines present in the environment in which they are initiated. Interleukin (IL)-12 and IL-23, cytokines induced during early stages of IBD, play important roles in differentiation of interferon (IFN)-γ/tumor necrosis factor (TNF)-producing Th1 cells as well as IL-17-producing Th17 cells. However, Th17 cells require additional signals including IL-6 and TGF-β for full induction of their differentiation. IL-6, in combination with TNF-α and tryptophan metabolites, initiates differentiation of protective IL-22-producing Th22 cells. Th1 differentiation is initiated and stabilized by transcription factors signal transducer and activator of transcription (STAT)4 and T-bet while Th17 cells require a combination of transcriptional regulators including STAT3, SMAD proteins, and RORγt. IL-4, IL-5, and IL-13-secreting Th2 and IL-9-secreting Th9 cells require IL-4 and STAT6 for their differentiation. Similar to Th17 cells, Th9 cells additionally require TGF-β, SMAD proteins, and a TGF-β/SMAD-induced transcription factor PU.1 for their development. As a whole, the inflammatory mediators produced by Th cells in IBD play a role in the maintenance or breaking down gut epithelial barriers or in recruiting unique cells types to the intestines that further promote inflammation. Factors in red indicate genes involved in Th cell differentiation or function that contain single nucleotide polymorphisms that are associated with increased disease susceptibility or severity in humans (see Table 2).