L-Selectin, α4β1, and α4β7 Integrins Participate in CD4+ T Cell Recruitment to Chronically Inflamed Small Intestine

Abstract

CD4+ T cells are essential for development and perpetuation of Crohn’s disease, a chronic immune-mediated condition that affects primarily the small intestine. Using novel models of Crohn’s disease-like ileitis (i.e., SAMP1/YitFc and CD4+ T cell transfer models), we have begun to understand the adhesive pathways that mediate lymphocyte trafficking to the chronically inflamed small bowel. Expansion of the CD4/β7+ population and increased mucosal addressin cell adhesion molecule-1 (MAdCAM-1) expression were observed within the intestinal lamina propria with disease progression. However, Ab blockade of the β7 integrin, the α4β7 heterodimer, MAdCAM-1, or L-selectin did not attenuate inflammation. Blockade of two pathways (L-selectin and MAdCAM-1 or α4 integrins) was required to improve ileitis. Further analyses showed that 55 ± 7% of the mesenteric lymph node α4β7+CD4 expressed L-selectin. These L-selectin+ T cells were the main producers of TNF-α and the predominant ileitis-inducing subpopulation. Mechanistically, combined blockade of L-selectin and MAdCAM-1 depleted the intestinal lamina propria of CD4+ T cells that aberrantly coexpressed α4β7 and α4β1 integrins, markedly decreasing local production of TNF-α and IFN-γ. Thus, pathogenic CD4+ T cells not only use the physiologic α4β7/MAdCAM-1 pathway, but alternatively engage α4β1 and L-selectin to recirculate to the chronically inflamed small intestine.

Phenotype and Effector Function of CC Chemokine Receptor 9-Expressing Lymphocytes in Small Intestinal Crohn’s Disease

“…CCL25-stimulated LPL or MLN lymphocyte-triggered adhesion to VCAM-1/Fc was as robust as that observed with Mn 2ϩ , which can directly activate the ␣ 4 ␤ 1 integrin. Murine studies have implicated an important role for MAdCAM-1, L-selectin, and VCAM-1 in the pathogenesis of experimental ileitis (24,25), indicating that additional pathways are operative in lymphocyte recruitment in the intestine in inflammatory vs homeostatic conditions. Blocking several integrins/ligands in some experimental models has been shown to be required for effective treatment of experimental IBD (24,25).…”

“…Murine studies have implicated an important role for MAdCAM-1, L-selectin, and VCAM-1 in the pathogenesis of experimental ileitis (24,25), indicating that additional pathways are operative in lymphocyte recruitment in the intestine in inflammatory vs homeostatic conditions. Blocking several integrins/ligands in some experimental models has been shown to be required for effective treatment of experimental IBD (24,25). This could explain the therapeutic efficacy of natalizumab (anti-␣ 4 integrin mAb) in CD by inhibiting the shared ␣ 4 integrin moiety of both ␣ 4 ␤ 1 and ␣ 4 ␤ 7 in effector cells (6).…”

Rôle et ciblage de l’intégrine α4β7 dans la physiopathologie des MICI et de l’infection par le VIH

“…Le rôle des chimiokines et de leurs récepteurs est très important. Ainsi, la liaison de CCL25 à CCR9 provoque des changements conformationnels de l'intégrine 47, et le blocage de cette interaction réduit l'iléite chronique chez la souris [5].…”

Early viral replication in lymph nodes provides HIV with a means by which to escape NK‐cell‐mediated control

“…In mice, recruitment of NK cells to LNs depends on CD62L and CXCR3 [32]. Furthermore, CCR1 [33], CCR5 [34,35], CCR7 [36], CXCR1 [37], CX 3 CR1 [38], LPAM-1 (a4b7 integrin) [39], and CD103 (aEb7 integrin) [40] have also been implicated in recruitment of NK cells to sites of inflammation. Surprisingly, NK cells in HIV 1 individuals exhibited reduced CX 3 CR1 (po0.01) and CXCR1 (po0.01) expression compared with uninfected controls, suggesting that despite HIV-associated inflammation, NK cells may have a reduced capacity to migrate to the LN due to reduced expression of chemokine receptors that are critical for homing to lymphoid tissues and sites of inflammation (Fig.…”