L-Selectin, α4β1, and α4β7 integrins participate in CD4+ T cell recruitment to chronically inflamed small intestine

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/beta(7)(+) 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 beta(7) integrin, the alpha(4)beta(7) heterodimer, MAdCAM-1, or L-selectin did not attenuate inflammation. Blockade of two pathways (L-selectin and MAdCAM-1 or alpha(4) integrins) was required to improve ileitis. Further analyses showed that 55 +/- 7% of the mesenteric lymph node alpha(4)beta(7)(+)CD4 expressed L-selectin. These L-selectin(+) T cells were the main producers of TNF-alpha 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 alpha(4)beta(7) and alpha(4)beta(1) integrins, markedly decreasing local production of TNF-alpha and IFN-gamma. Thus, pathogenic CD4(+) T cells not only use the physiologic alpha(4)beta(7)/MAdCAM-1 pathway, but alternatively engage alpha(4)beta(1), and L-selectin to recirculate to the chronically inflamed small intestine. The Journal of Immunology, 2005, 174: 2343-2352.