L-selectin, alpha 4 beta 1, and alpha 4 beta 7 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/beta7+ 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 beta7 integrin, the alpha4beta7 heterodimer, MAdCAM-1, or L-selectin did not attenuate inflammation. Blockade of two pathways (L-selectin and MAdCAM-1 or alpha4 integrins) was required to improve ileitis. Further analyses showed that 55 +/- 7% of the mesenteric lymph node alpha4beta7+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 alpha4beta7 and alpha4beta1 integrins, markedly decreasing local production of TNF-alpha and IFN-gamma. Thus, pathogenic CD4+ T cells not only use the physiologic alpha4beta7/MAdCAM-1 pathway, but alternatively engage alpha4beta1 and L-selectin to recirculate to the chronically inflamed small intestine.

• Authors: Jesús Rivera-Nieves, Timothy Olson, Giorgos Bamias, Anthony Bruce, Michael Solga, Robert F Knight, Sharon Hoang, Fabio Cominelli, Klaus Ley
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 174 Issue 4 Pg. 2343-52 (Feb 15 2005) ISSN: 0022-1767 [Print] United States
• PMID: 15699171 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antibodies, Blocking
• Cell Adhesion Molecules
• Immunoglobulins
• Integrin alpha4beta1
• Integrins
• Madcam1 protein, mouse
• Mucoproteins
• Tumor Necrosis Factor-alpha
• integrin alpha4beta7
• L-Selectin

Topics

• Animals
• Antibodies, Blocking (administration & dosage)
• CD4-Positive T-Lymphocytes (immunology, metabolism, pathology)
• Cell Adhesion Molecules
• Cell Movement (immunology)
• Chronic Disease
• Disease Progression
• Female
• Ileitis (genetics, immunology, pathology)
• Immunoglobulins (biosynthesis)
• Integrin alpha4beta1 (biosynthesis, physiology)
• Integrins (antagonists & inhibitors, biosynthesis, physiology)
• L-Selectin (biosynthesis, immunology, physiology)
• Male
• Mice
• Mice, Inbred AKR
• Mice, Mutant Strains
• Mice, SCID
• Mucoproteins (antagonists & inhibitors, biosynthesis)
• Signal Transduction (immunology)
• Tumor Necrosis Factor-alpha (biosynthesis)
• Up-Regulation (genetics, immunology)