CD40-mediated immune-nonimmune cell interactions induce mucosal fibroblast chemokines leading to T-cell transmigration

Gastroenterology. 2004 Jan;126(1):63-80. doi: 10.1053/j.gastro.2003.10.046.


Background and aims: The CD40 pathway is a key mediator of inflammation and autoimmunity. We investigated cell adhesion molecule (CAM) up-regulation and chemokine production by CD40-positive human intestinal fibroblasts (HIF) and microvascular endothelial cells (HIMEC) induced by CD40 ligand (CD40L)-positive T cells and soluble CD40L and their effect on T-cell adhesion and transmigration.

Methods: Expression of CD40, CD40L, and CAM was assessed by immunohistochemistry, confocal microscopy and flow cytometric analysis, and chemokine production using enzyme-linked immunosorbent assay. Calcein-labeled T cells were used to assay HIF adhesion and Transwell HIMEC transmigration.

Results: Ligation of CD40-positive HIF and HIMEC by CD40L-positive T cells or soluble CD40L induced up-regulation of CAM expression as well as interleukin-8 and RANTES production. The specificity of these responses was shown by inhibition with a CD40L blocking antibody and by CD40 signaling-dependent p38 mitogen-activated protein kinase phosphorylation. On CD40 ligation, HIF increased their T-cell binding capacity and generated chemoattractants able to induce T-cell migration through HIMEC monolayers.

Conclusions: Activation of the CD40/CD40L system in the gut mucosa may trigger a self-sustaining loop of immune-nonimmune cell interactions leading to an antigen-independent influx of T cells that contributes to chronic inflammation.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • CD40 Antigens / administration & dosage
  • CD40 Antigens / metabolism*
  • CD40 Ligand / metabolism
  • Case-Control Studies
  • Cell Adhesion Molecules / metabolism
  • Cell Communication*
  • Cell Movement
  • Cells, Cultured
  • Chemokines / metabolism*
  • Chemotactic Factors / metabolism
  • Colon / pathology
  • Colon / physiopathology
  • Dose-Response Relationship, Drug
  • Endothelium, Vascular / pathology
  • Endothelium, Vascular / physiopathology
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism*
  • Humans
  • Immune System / physiopathology*
  • Inflammatory Bowel Diseases / pathology
  • Inflammatory Bowel Diseases / physiopathology*
  • Intestinal Mucosa / metabolism*
  • Intestinal Mucosa / pathology
  • Intestines / blood supply
  • Microcirculation
  • Mitogen-Activated Protein Kinases / metabolism
  • Phosphorylation / drug effects
  • T-Lymphocytes* / metabolism
  • p38 Mitogen-Activated Protein Kinases


  • CD40 Antigens
  • Cell Adhesion Molecules
  • Chemokines
  • Chemotactic Factors
  • CD40 Ligand
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases