L-selectin, α₄β₁, and α ₄β₇ 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/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 α₄β₇CD4 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 α₄β ₇ and α₄β₁ integrins, markedly decreasing local production of TNF-α and IFN-γ. Thus, pathogenic CD4⁺ T cells not only use the physiologic α₄β ₇/MAdCAM-1 pathway, but alternatively engage α ₄β₁ and L-selectin to recirculate to the chronically inflamed small intestine.