T lymphocytes in the intestinal mucosa: defense and tolerance

Abstract

Although lymphocytes are known to circulate throughout lymphoid tissues and blood, they also establish residency in nonlymphoid organs, most prominently in barrier tissues, such as the intestines. The adaptation of T lymphocytes to intestinal environments requires constant discrimination between natural stimulation from commensal flora and food and pathogens that need to be cleared. Genetic variations that cause a defective defense or a break in tolerance along with environmental cues, such as infection or imbalances in the gut microbiota known as dysbiosis, can trigger several immune disorders via the activation of T lymphocytes in the intestines. Elucidation of the immune mechanisms that distinguish between commensal flora and pathogenic organisms may reveal therapeutic targets for the prevention or modulation of inflammatory diseases and boost the efficacy of cancer immunotherapy. In this review, we discuss the development and adaptation of T lymphocytes in the intestine, how these cells protect the host against pathogenic infections while tolerating food antigens and commensal microbiota, and the potential implications of targeting these cells for disease management and therapeutics.

Keywords: Gut microbiota; Intestinal T cells; Pathogenic infection; T-cell therapy.

Fig. 1

Development and maturation of intestinal T lymphocytes. Intestinal T cells can be classified as induced “conventional” (or “type a”) intestinal T cells or “nonconventional” (or “type b”) intestinal T cells. Conventional intestinal T cells express TCRαβ and CD4 or CD8αβ and serve as TCR coreceptors. Nonconventional intestinal T cells express either TCRαβ or TCRγδ and typically also express CD8αα homodimers. Conventional T cells are derived from CD4⁻CD8⁻(DN) progenitors in the thymus and develop into SP CD4⁺T (MHC I) cells or CD8⁺ T cells (MHC II). These cells subsequently migrate to peripheral lymphoid organs, such as the lymph nodes, where they encounter antigens and acquire an activated effector phenotype that drives their migration to the gut. Alternatively, immature triple-negative thymocytes (CD4⁻CD8⁻TCR⁻) in the thymus differentiate into double-negative (CD4⁻CD8⁻), TCRγδ-positive or TCRαβ-positive intestinal T-cell precursors. TCRαβ-positive T-cell precursors partially acquire their antigen-experienced phenotype during selection by self-antigens presented by thymic stromal cells. The upregulation of gut-homing-associated molecules, including the integrin α4β7, the chemokine receptor CCR9, and CD8αα homodimers, guide these TCRγδ-positive or TCRαβ-positive T-cell precursors to the intestine. For instance, T cells are attracted by the chemokine CCL25 (ligand of CCR9) secreted by the intestinal epithelial cells. In the gut, an environment abundant in microbial and food antigens presented by dendritic cells (DCs) can shape diverse functionally specialized T-cell populations with remarkable plasticity to trans-differentiate into T cells bearing other features, even with opposing functions. Factors secreted by epithelial or other intestinal cells, such as IL-15 and retinal acid (RA), promote the retention of T cells in the intestine

Fig. 2

Regulation of T lymphocytes by microbial signals in the intestine. Due to frequent exposure to large numbers of foreign antigens, a robust but regulated immune response is key to maintaining intestinal homeostasis. CD4-positive T helper cells express cytokines with diverse functions and are central responders to microbial signals by either initiating the inflammatory response to fight against pathogens or shaping an environment tolerable of commensals and food antigens. CD8⁺ T cells are activated by DC-presented antigens and kill infected or damaged cells. RAR-related orphan receptor (ROR)γt-positive Th17 cells, which account for 30–40% of differentiated memory CD4⁺ T cells in the lamina propria (LP), are key effector T cells. Under homeostatic conditions, Th17 cells produce cytokines, such as IL-17A, IL-17F, and IL-22, which protect the host from bacterial invasion by stimulating the production of antimicrobial proteins and contribution to the formation of tight junctions between intestinal epithelial cells. However, exposure to dietary antigens or the overgrowth of inflammatory bacteria initiates the differentiation of naive CD4⁺ T cells into pathogenic effector T cells. In cases of dysbiosis, Th17 cells become pathogenic and produce IFN-γ and GM-CSF when stimulated by IL-23 and IL-1β, thus promoting inflammatory or autoimmune diseases. Another important T-cell population, i.e., regulatory T cells (Tregs), exists in the intestine to maintain homeostasis by balancing inflammatory effects or inducing the tolerant response to antigens from commensals or food. One subset of Helios and receptor neuropilin 1 (Nrp1)-positive Tregs are thymus-derived (tTregs). Another subset of Helios and Nrp1-negative Tregs are peripherally differentiated Treg (pTregs). Colonic pTregs induced by antigens and metabolites are produced by commensal bacteria, whereas pTregs in the small intestine are mainly maintained by food antigens. GM-CSF granulocyte-macrophage colony-stimulating factor