L-selectin, alpha 4 beta 1, and alpha 4 beta 7 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/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.
Rivera-Nieves
Jesús
J
Digestive Health Center of Excellence, University of Virginia Health Sciences Center, Charlottesville, VA 22908, USA. jr3u@virginia.edu
Olson
Timothy
T
Bamias
Giorgos
G
Bruce
Anthony
A
Solga
Michael
M
Knight
Robert F
RF
Hoang
Sharon
S
Cominelli
Fabio
F
Ley
Klaus
K
D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D015815:Cell Adhesion Molecules; D002465:Cell Movement / Q000276:immunology*; D002908:Chronic Disease; D018450:Disease Progression; D005260:Female; D007079:Ileitis / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D007136:Immunoglobulins / Q000096:biosynthesis; D039041:Integrin alpha4beta1 / Q000096:biosynthesis / Q000502:physiology*; D016023:Integrins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D019041:L-Selectin / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*; D008297:Male; D051379:Mice; D008806:Mice, Inbred AKR; D008817:Mice, Mutant Strains; D016513:Mice, SCID; D009088:Mucoproteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015398:Signal Transduction / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
D019138:Antibodies, Blocking; D015815:Cell Adhesion Molecules; D007136:Immunoglobulins; D039041:Integrin alpha4beta1; D016023:Integrins; C489082:Madcam1 protein, mouse; D009088:Mucoproteins; D014409:Tumor Necrosis Factor-alpha; C071777:integrin alpha4beta7; D019041:L-Selectin