IL-10 downregulates CXCR3 expression on Th1 cells and interferes with their migration to intestinal inflammatory sites

M Wadwa; R Klopfleisch; A Adamczyk; A Frede; E Pastille; K Mahnke; W Hansen; R Geffers; K S Lang; J Buer; J Büning; A M Westendorf

doi:10.1038/mi.2015.132

IL-10 downregulates CXCR3 expression on Th1 cells and interferes with their migration to intestinal inflammatory sites

Mucosal Immunol. 2016 Sep;9(5):1263-77. doi: 10.1038/mi.2015.132. Epub 2016 Jan 6.

Authors

M Wadwa¹, R Klopfleisch², A Adamczyk¹, A Frede¹, E Pastille¹, K Mahnke³, W Hansen¹, R Geffers⁴, K S Lang⁵, J Buer¹, J Büning⁶, A M Westendorf¹

Affiliations

¹ Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
² Institute of Veterinary Pathology, Freie Universität Berlin, Berlin, Germany.
³ Department of Dermatology, Ruprecht-Karls University Heidelberg, Heidelberg, Germany.
⁴ Genome Analytics, Helmholtz Centre for Infection Research, Braunschweig, Germany.
⁵ Institute of Immunology, Medical Faculty, University of Duisburg-Essen, Essen, Germany.
⁶ Department of Internal Medicine I, University Hospital of Schleswig-Holstein, Lübeck, Germany.

PMID: 26732675
DOI: 10.1038/mi.2015.132

Abstract

Inflammatory bowel disease (IBD) is characterized by chronic, uncontrolled inflammation in the intestinal mucosa. Although the etiology is poorly understood, it is widely accepted that loss of tolerance is involved in the development of IBD. Therefore, re-establishing tolerance or gut homeostasis is one of the key features in the development of new therapeutic strategies. Here we show that antigen targeting to DEC-205 on dendritic cells leads to an interleukin (IL)-10-dependent downregulation of C-X-C chemokine receptor 3 (CXCR3) expression on differentiated antigen-specific T helper type 1 (Th1) cells in vivo. This downregulation interferes with the migration of Th1 cells into the gut and protects mice against severe acute and relapsing intestinal inflammation. Moreover, CD4(+)CXCR3(+) T cells are highly enriched in the inflamed mucosa of IBD patients. Interference with this pathway may therefore be a promising approach for the treatment of IBD. In conclusion, we propose a hitherto undescribed mechanism by which IL-10 can act on effector T cells and orchestrate intestinal immune responses.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antigens, CD / genetics
Antigens, CD / immunology*
CD4 Antigens / genetics
CD4 Antigens / immunology
Cell Movement
Colitis, Ulcerative / genetics
Colitis, Ulcerative / immunology*
Colitis, Ulcerative / pathology
Crohn Disease / genetics
Crohn Disease / immunology*
Crohn Disease / pathology
Dendritic Cells / immunology
Dendritic Cells / pathology
Gene Expression Regulation
Humans
Immune Tolerance
Interleukin-10 / genetics
Interleukin-10 / immunology*
Intestinal Mucosa / immunology
Intestinal Mucosa / pathology
Lectins, C-Type / genetics
Lectins, C-Type / immunology*
Mice
Mice, Inbred BALB C
Mice, Transgenic
Minor Histocompatibility Antigens / genetics
Minor Histocompatibility Antigens / immunology*
Receptors, CXCR3 / genetics
Receptors, CXCR3 / immunology*
Receptors, Cell Surface / genetics
Receptors, Cell Surface / immunology*
Signal Transduction
Th1 Cells / immunology*
Th1 Cells / pathology

Substances

Antigens, CD
CD4 Antigens
Cxcr3 protein, mouse
DEC-205 receptor
IL10 protein, mouse
Lectins, C-Type
Minor Histocompatibility Antigens
Receptors, CXCR3
Receptors, Cell Surface
Interleukin-10