Intestinal effector T cells in health and disease

Abstract

Crohn's disease and ulcerative colitis are the two major forms of chronic relapsing inflammatory disorders of the human intestines collectively referred to as inflammatory bowel disease (IBD). Though a complex set of autoinflammatory disorders that can be precipitated by diverse genetic and environmental factors, a feature that appears common to IBD pathogenesis is a dysregulated effector T cell response to the commensal microbiota. Due to the heightened effector T cell activity in IBD, developmental and functional pathways that give rise to these cells are potential targets for therapeutic intervention. In this review, we highlight recent advances in our understanding of effector T cell biology in the context of intestinal immune regulation and speculate on their potential clinical significance.

Figure 1. Mechanisms inhibiting the development and local function of intestinal effector CD4⁺ T cells

The intestinal epithelium serves as a physical barrier between the intestinal lumen and the lamina propria. Intestinal epithelial cells (IECs) secrete antimicrobial peptides, and goblet cells (not shown) secrete mucous that forms a barrier on the epithelial surface. IECs sense microbederived substances and respond with production of anti-inflammatory cytokines such as TSLP, IL-25, TGF-β and IL-10. IL-10, which is produced by multiple cell types in the intestines, down-regulates APC expression of MHC II, adhesion molecules (eg, ICAM-1), co-stimulatory molecules (eg, CD80 and CD86), and pro-inflammatory cytokines (eg, IL6, IL-23 or IL-12), thereby inhibiting effector T cell (T_E) activation. Both IL-10 and TGF-β can induce high amounts of the negative regulator CD200 receptor (CD200R) on tissue macrophages in the small intestine. As a product of effector T cell lineages, IL-10 can also act in an autocrine manner to down-regulate effector T cell responses. Locally activated TGF-β suppresses both the development and function of effector T cells via APC- and/or T cell-directed mechanisms, and promotes iTreg (T_R) development (in the absence of pro-inflammatory factors). Active TGF-β also promotes B cell immunoglobulin (Ig) isotype class switching, resulting in the secretion of flora-reactive IgA which is translocated across IECs in association with J-chain into the intestinal lumen, thereby sequestering bacterial antigens from mucosal APCs.

Figure 2. Possible mechanisms of induction and control of intestinal T cell lineage development

Activation of intestinal APCs by commensal microbes acquired by direct sampling of the luminal contents or via ingestion of transcytosed or invading microbes results in secretion of pro-inflammatory cytokines, such as IL-6, IL-23, and IL-27. Along with TGF-β, IL-6 induces differentiation of a population of Foxp3 and RORγt ‘double-positive precursor’ cells, which express low amounts of both transcription factors. Sustained or increased TGF-β stimulation coupled with reduced IL-6 signaling in the presence of retinoic acid (RA) skews this population towards increased, stable expression of Foxp3 and down-regulation of RORγt and the Th17 program. Conversely, lower amounts of TGF-β signaling in the continued presence of IL-6 favor down-regulation of Foxp3 and divergence towards RORγt-expressing Th17 cells. IL-27 can inhibit Th17 development while directly promoting STAT1-driven differentiation of Th1 effectors. IL-23 produced by TLR and/or NLR-activated APCs promotes late stages of pro-inflammatory Th17 effector functions. Intestinal Th1 cells might emerge from Th17 precursors, or develop independently of the Th17 pathway. Commensal antigen stimulation of IECs induces expression of TSLP and IL-25, which can inhibit Th17 maintenance by suppressing local expression of IL-23.