Tissue-Resident T Cells in Chronic Relapsing-Remitting Intestinal Disorders

Abstract

Tissue-resident memory T (T_RM) cells critically contribute to the rapid immunoprotection and efficient immunosurveillance against pathogens, particularly in barrier tissues, but also during anti-tumor responses. However, the involvement of T_RM cells also in the induction and exacerbation of immunopathologies, notably in chronically relapsing auto-inflammatory disorders, is becoming increasingly recognized as a critical factor. Thus, T_RM cells may also represent an attractive target in the management of chronic (auto-) inflammatory disorders, including multiple sclerosis, rheumatoid arthritis, celiac disease and inflammatory bowel diseases. In this review, we focus on current concepts of T_RM cell biology, particularly in the intestine, and discuss recent findings on their involvement in chronic relapsing-remitting inflammatory disorders. Potential therapeutic strategies to interfere with these T_RM cell-mediated immunopathologies are discussed.

Keywords: T cell retention; circulating T cells; intestinal inflammation; memory T cells; tissue-resident T cells.

Figure 1

Activation of conventional intestinal T cells following primary exposure to a novel, MHC-restricted antigen versus re-exposure of T_RM cells to their cognate antigen. (1) Intestinal lumen-derived antigens (microbiota, food antigens, pathogens) breach the intestinal epithelial barrier through specialized M cells overlying intestinal Peyer’s patches and solitary follicles (not shown), or obtain access to the intestinal lamina propria when the integrity of the epithelial layer is disrupted. Inside the lamina propria, antigens are rapidly taken up and digested by local macrophages, which are rather poor antigen-presenting cells. A fraction of the intestinal lumen-derived antigens, however, is sampled by intestinal dendritic cells. (2) These antigen-loaded dendritic cells become activated and migrate to the draining mesenteric lymph nodes, (3) where they present the antigen in an MHC-restricted manner to antigen-specific naïve CCR7⁺ CD62L⁺ T cells. (4) Upon their priming in the draining lymph nodes, these activated T cells acquire a gut homing phenotype, characterized by the cell surface expression of α4β7 and CCR9, which bind to MadCAM-1 expressed on gut-associated endothelial cells, and to the chemokine CCL25, secreted by endothelial cells in the small intestine and by follicle-associated epithelium of Peyer’s patches, respectively. This imprinted phenotype allows the primed T cells to home back to the site of initial antigen breaching. (5) Under the influence of the local intestinal microenvironment (e.g., TGF-β, IL-12 and type-I IFN), some of these recently activated T cells acquire a T_RM cell signature. (6) Within the intestinal mucosa, transcription of the α4 chain gene is suppressed in T cells. TGF-β, secreted by macrophages and dendritic cells, induces the expression of αE integrin (CD103). The αEβ7 heterodimer binds to E-cadherin, which is expressed on epithelial cells and subsets of dendritic cells. Subsets of CD8⁺ T_RM cells also express the integrin α1 chain together with the β1 integrin (α1β1), which directly binds to type I and IV collagen and, hence, supports the adherence and retention of T_RM cells in skin, lung and intestine. Most T_RM cells also express CD69, which antagonizes S1P₁ (Sphingosine 1 phosphate receptor-1), thus contributing to their retention within the tissue. RGS1, which attenuates signaling via Gαi- or Gαq- linked G-protein-coupled receptors, is also highly expressed in T_RM cells. This signature allows them to remain at this site even upon complete clearance of their cognate antigen. These newly generated T_RM cells will thus continuously expand the existing repertoire of antigen specificities of the local T_RM cells. Some of these activated T_RM cells (mostly CD8αβ⁺ TCRαβ⁺, CD8αα⁺ TCRαβ⁺ and TCRγδ⁺ cells) will home to the intestinal epithelium (“intraepithelial lymphocytes”), where they are preferentially retained by the interaction of the αEβ7 integrin on their surface with epithelial cell-expressed E-cadherin. (7) Upon re-exposure to the cognate antigen, T_RM cells are rapidly activated and expand locally in the mucosa. They are prone to efficiently secrete cytokines and express cell surface molecules, which may further enhance the uptake and degradation of incoming microbes or dietary compounds by local (resident) macrophages. Reactivated T_RM cells may express cytotoxic effector molecules, including granzymes and perforin, or secrete chemokines that promote the recruitment of other leukocyte subsets, including monocytes, but also effector T cells. (8) Additionally they can loose some T_RM cell markers and retention profile (Hobit, CD69, and potentially RGS1) and upregulate genes related to egress (S1pr1). (9) Thus, eventually, they can re-enter the blood circulation as “ex-T_RM” cells, becoming circulating effector cells and memory T cells, thus, supporting also the systemic immune response.