Leukocyte Trafficking to the Small Intestine and Colon

Abstract

Leukocyte trafficking to the small and large intestines is tightly controlled to maintain intestinal immune homeostasis, mediate immune responses, and regulate inflammation. A wide array of chemoattractants, chemoattractant receptors, and adhesion molecules expressed by leukocytes, mucosal endothelium, epithelium, and stromal cells controls leukocyte recruitment and microenvironmental localization in intestine and in the gut-associated lymphoid tissues (GALTs). Naive lymphocytes traffic to the gut-draining mesenteric lymph nodes where they undergo antigen-induced activation and priming; these processes determine their memory/effector phenotypes and imprint them with the capacity to migrate via the lymph and blood to the intestines. Mechanisms of T-cell recruitment to GALT and of T cells and plasmablasts to the small intestine are well described. Recent advances include the discovery of an unexpected role for lectin CD22 as a B-cell homing receptor GALT, and identification of the orphan G-protein-coupled receptor 15 (GPR15) as a T-cell chemoattractant/trafficking receptor for the colon. GPR15 decorates distinct subsets of T cells in mice and humans, a difference in species that could affect translation of the results of mouse colitis models to humans. Clinical studies with antibodies to integrin α4β7 and its vascular ligand mucosal vascular addressin cell adhesion molecule 1 are proving the value of lymphocyte trafficking mechanisms as therapeutic targets for inflammatory bowel diseases. In contrast to lymphocytes, cells of the innate immune system express adhesion and chemoattractant receptors that allow them to migrate directly to effector tissue sites during inflammation. We review the mechanisms for innate and adaptive leukocyte localization to the intestinal tract and GALT, and discuss their relevance to human intestinal homeostasis and inflammation.

Keywords: Adhesion Molecules; Chemokine Receptors; Intestine; Leukocyte Trafficking.

Figure 1

Small intestine and colon homing of lymphocytes. Antigens in the intestine are captured and processed by intestinal mononuclear phagocytes (MP), which include macrophages and DCs. DCs that have taken up antigen then up-regulate CCR7 expression, which directs their migration to GALT (eg, MLN) where they induce differentiation of naive T cells (T_N) into regulatory or effector T cells (T_E), and imprint them with trafficking receptors that direct them to the intestines. Localization of T and B cells to the small intestine (left) is mediated by α4β7 (which binds the vascular addressin MADCAM1) and CCR9. Expression of CCR10 together with α4β7 targets plasmablasts to the large intestine. Expression of α4β7 and GPR15, as well as additional chemoattractant receptor(s), mediates T-cell homing to the colon (right). As discussed in the text, CCR6 can direct T-cell recruitment to the intestines during inflammation but not during homeostasis; CCR5 may help direct Treg recruitment to the chronically inflamed distal small intestine, and CXCR4 may contribute to T-cell localization to the small and large intestine (gray letters).

Figure 2

Model of the control of T-cell expression of GPR15 in mice and humans. In the model, the colon provides signals (potentially presented by colon-derived DCs in draining lymph nodes) that induce differentiation of T_N cells into Th2 or Treg cells and also their expression of α4β7. Additional signals, including transforming growth factor (TGF)β, and products derived directly or indirectly from intestinal microbiota up-regulate GPR15 expression on Th2 cells in humans, but on Tregs (and Th17 cells, not shown) in the mouse. Expression of GPR15 is regulated by transcription factor binding to 3 prime GPR15 enhancer sequences. In human Th2 cells (top left), GATA3, a positive regulator of Th2 cell-specific transcription, binds to enhancer sequences to activate expression of GPR15. In human Tregs (bottom left), the transcriptional repressor FOXP3 binds this enhancer region strongly, reducing expression of GPR15 in activated (FOXP3⁺) Tregs in the normal or inflamed colon. In contrast, altered enhancer sequences in the mouse do not bind GATA3, so that transcription is not activated in mouse Th2 cells (top right), and bind Foxp3 only poorly, allowing expression in Tregs (bottom right). Although other regions of the gene and regulators clearly are involved, the differences in enhancer binding by these important transcriptional regulators likely mediates the differences in GPR15 expression observed in human vs mouse T cells. These differences would affect translation of findings from mouse studies to humans.