CD46-induced immunomodulatory CD4+ T cells express the adhesion molecule and chemokine receptor pattern of intestinal T cells.
Tissue homing of activated T cells is typically mediated through their specific integrin and chemokine receptor repertoire. Activation of human primary CD4(+) T cells in the presence of CD46 cross-linking induces the development of a distinct immunomodulatory T cell population characterized by high IL-10/granzyme B production. How these regulatory T cells (Tregs) migrate/home to specific tissue sites is not understood. In this study, we determined the adhesion protein and chemokine receptor expression pattern on human CD3/CD46-activated peripheral blood CD4(+) T cells. CD3/CD46-activated, but not CD3/CD28-activated, T cells up-regulate the integrin alpha(4)beta(7). The interaction of alpha(4)beta(7) with its ligand mucosal addressin cell adhesion molecule 1 (MAdCAM-1) mediates homing or retention of T cells to the intestine. CD3/CD46-activated Tregs adhere to/roll on MAdCAM-1-expressing HeLa cells, similar to T cells isolated from the human lamina propria (LP). This interaction is inhibited by silencing MAdCAM-1 expression in HeLa cells or by the addition of blocking Abs to beta(7). CD46 activation of T cells also induced the expression of the surface-bound cytokine LIGHT and the chemokine receptor CCR9, both marker constitutively expressed by gut LP-resident T cells. In addition, we found that approximately 10% of the CD4(+) T lymphocytes isolated from the LP of patients undergoing bariatric surgery contain T cells that spontaneously secrete a cytokine pattern consistent with that from CD46-activated T cells. These data suggest that CD46-induced Tregs might play a role in intestinal immune homeostasis where they could dampen unwanted effector T cell responses through local IL-10/granzyme B production.
Alford
Shannon K
SK
Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Longmore
Gregory D
GD
Stenson
William F
WF
Kemper
Claudia
C
D015815:Cell Adhesion Molecules; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D053804:Granzymes / Q000096:biosynthesis / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D007136:Immunoglobulins / Q000096:biosynthesis / Q000502:physiology; D016023:Integrins / Q000096:biosynthesis / Q000502:physiology; D016753:Interleukin-10 / Q000096:biosynthesis / Q000378:metabolism; D007413:Intestinal Mucosa / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology*; D051916:Membrane Cofactor Protein / Q000502:physiology*; D009088:Mucoproteins / Q000096:biosynthesis / Q000502:physiology; D019707:Receptors, Chemokine / Q000096:biosynthesis* / Q000235:genetics; D016201:Receptors, Lymphocyte Homing / Q000096:biosynthesis* / Q000502:physiology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*; D015854:Up-Regulation / Q000276:immunology
C497857:CD46 protein, human; D015815:Cell Adhesion Molecules; D007136:Immunoglobulins; D016023:Integrins; C504265:MADCAM1 protein, human; D051916:Membrane Cofactor Protein; D009088:Mucoproteins; D019707:Receptors, Chemokine; D016201:Receptors, Lymphocyte Homing; C071777:integrin alpha4beta7; D016753:Interleukin-10; D053804:Granzymes