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Updated: May 5, 2026
Imaging CD4 T Cell Interstitial Migration in the Inflamed Dermis
Published on: March 25, 2016
CD40-mediated immune-nonimmune cell interactions induce mucosal fibroblast chemokines leading to T-cell
Jon D Vogel1, Gail A West, Silvio Danese
1Division of Gastroenterology, University Hospitals of Cleveland, Case Western University School of Medicine, Cleveland, OH 44106, USA.
Insights
The CD40/CD40L pathway in the gut promotes T-cell adhesion and migration by up-regulating cell adhesion molecules and chemokines, contributing to chronic inflammation.
Area of Science:
- Immunology
- Gastroenterology
- Cell Biology
Background:
- The CD40 pathway is crucial in regulating inflammation and autoimmunity.
- Immune and non-immune cells interact within the gut mucosa.
Purpose of the Study:
- To investigate how CD40 ligand (CD40L) on T cells and soluble CD40L affect CD40-positive human intestinal fibroblasts (HIF) and microvascular endothelial cells (HIMEC).
- To determine the impact on cell adhesion molecule (CAM) expression, chemokine production, and T-cell migration in the gut.
Main Methods:
- Immunohistochemistry, confocal microscopy, and flow cytometry were used to assess CD40, CD40L, and CAM expression.
- Enzyme-linked immunosorbent assay measured chemokine production (interleukin-8, RANTES).
- Calcein-labeled T cells assessed adhesion to HIF and transmigration through HIMEC.
Main Results:
- CD40 ligation by CD40L upregulated CAMs and induced interleukin-8 and RANTES production in HIF and HIMEC.
- These responses were specific, confirmed by CD40L blocking antibodies and p38 MAPK phosphorylation.
- HIF increased T-cell binding and produced chemoattractants, promoting T-cell migration through HIMEC.
Conclusions:
- Activation of the CD40/CD40L system in the gut mucosa can initiate a feedback loop.
- This loop involves immune-nonimmune cell interactions, leading to antigen-independent T-cell influx.
- This process contributes to the development and perpetuation of chronic gut inflammation.
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.
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