CD46-induced immunomodulatory CD4+ T cells express the adhesion molecule and chemokine receptor pattern of intestinal T cells

J Immunol. 2008 Aug 15;181(4):2544-55. doi: 10.4049/jimmunol.181.4.2544.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Adhesion Molecules
  • Cells, Cultured
  • Chemotaxis, Leukocyte / immunology
  • Granzymes / biosynthesis
  • Granzymes / physiology
  • HeLa Cells
  • Humans
  • Immunoglobulins / biosynthesis
  • Immunoglobulins / physiology
  • Integrins / biosynthesis
  • Integrins / physiology
  • Interleukin-10 / biosynthesis
  • Interleukin-10 / metabolism
  • Intestinal Mucosa / cytology
  • Intestinal Mucosa / immunology*
  • Intestinal Mucosa / metabolism*
  • Lymphocyte Activation / immunology*
  • Membrane Cofactor Protein / physiology*
  • Mucoproteins / biosynthesis
  • Mucoproteins / physiology
  • Receptors, Chemokine / biosynthesis*
  • Receptors, Chemokine / genetics
  • Receptors, Lymphocyte Homing / biosynthesis*
  • Receptors, Lymphocyte Homing / physiology
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism*
  • Up-Regulation / immunology

Substances

  • CD46 protein, human
  • Cell Adhesion Molecules
  • Immunoglobulins
  • Integrins
  • MADCAM1 protein, human
  • Membrane Cofactor Protein
  • Mucoproteins
  • Receptors, Chemokine
  • Receptors, Lymphocyte Homing
  • integrin alpha4beta7
  • Interleukin-10
  • Granzymes