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Role of beta7 integrins in intestinal lymphocyte homing and retention - PubMed

Review

Role of beta7 integrins in intestinal lymphocyte homing and retention

G Gorfu et al. Curr Mol Med. 2009 Sep.

Abstract

Lymphocytes involved in intestinal immune response are found in organized immune inductive sites of the gut-associated lymphoid tissues (GALT) such as Peyer's patches (PP), mesenteric lymph nodes (MLN) and diffuse effector sites of gut epithelium and lamina propria (LP). beta(7) integrins are responsible for efficient trafficking and retention of lymphocytes in these sites. Naïve and effector lymphocytes use alpha(4)beta(7) integrin to extravasate from blood to gut mucosal tissues of GALT, MLN and LP via interactions with Mucosal Addressin Cell Adhesion Molecule-1 (MAdCAM-1). The alpha(E)beta(7) integrin facilitates retention of effector and memory lymphocytes in the gut epithelial layer via interactions with E-cadherin. Mucosal dendritic cells (DCs) regulate the expression of the gut homing receptors alpha(4)beta(7) integrin and the chemokine receptor CCR9 on activated effector and regulatory lymphocytes in a retinoic acid-dependent manner. CD103 (alpha(E) integrin) identifies a subset of mucosal DCs in MLN and small intestine LP that have an enhanced ability to induce gut-tropic receptors on responding lymphocytes. The interactions between beta(7) integrin and their ligands are also implicated in the pathogenesis and progression of inflammatory bowel diseases (IBDs), intestinal parasitic infections and graft-versus-host diseases. During intestinal inflammation, beta(7) integrin-dependent and -independent pathways contribute to lymphocytes recruitment to the intestinal tissues and disease pat-hogenesis. Recent works have explored the potential of therapeutic targeting of alpha(4) and beta(7) integrins in IBDs. Here, we review the current understanding of the role of beta(7) integrins in intestinal lymphocyte trafficking and retention in health and disease.

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Conflict of interest statement

Conflict of interest The authors declare no competing financial interests.

Figures

Fig. (1)
Fig. (1). Role of β7 integrins in intestinal lymphocyte homing and retention

Lymphocytes involved in the intestinal immune response are organized in two compartments: inductive (A) and effector (B) sites. (A) Naïve lymphocytes (round cells) enter inductive sites through HEVs (polygonal) in PPs and MLNs, where they roll through L-selectin interactions with PNAd and become activated by surface-bound CCL19 and CCL21 that bind to CCR7. Lymphocyte α4β7 integrin interacts with MAdCAM-1 to mediate rolling and, after activation, firm adhesion. Once transmigrated into the parenchyma, lymphocytes encounter dendritic cells presenting antigen in the T cell zone of PP and MLN. RA produced by CD103 (αE)+ dendritic cells induce or enhance expression of gut-trophic receptors α4β7 integrin and CCR9 chemokine receptor. Once activated in PP, the mucosal lymphoblasts then enter the gut-draining MLN. (B) When effector cells return back to the intestinal LP, CCR9+α4β7 + activated lymphocytes preferentially leave the circulation via MAdCAM-1 and CCL25 (small circles) expressing LP-associated post-capillary venuels. Some of these α4β7 +CCR9+ LPLs are then destined to reside in the intestinal epithelium, attracted by CCL25. Switching from α4β7 + LPL to αEβ7+ IEL occurs by the effect of TGF-β, locally secreted by intestinal epithelium (cuboidal). As a result, most IELs express only αEβ7 integrin. The αEβ7+ IEL cells reside between epithelial cells via interaction with E-cadherin and this interaction is likely promoted by CCR9/CCL25 signaling. Thick arrows indicate migration; thin arrows indicate secretion of soluble mediators.

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