The early activation marker CD69 regulates the expression of chemokines and CD4 T cell accumulation in intestine

PLoS One. 2013 Jun 12;8(6):e65413. doi: 10.1371/journal.pone.0065413. Print 2013.

Abstract

Migration of naïve and activated lymphocytes is regulated by the expression of various molecules such as chemokine receptors and ligands. CD69, the early activation marker of C-type lectin domain family, is also shown to regulate the lymphocyte migration by affecting their egress from the thymus and secondary lymphoid organs. Here, we aimed to investigate the role of CD69 in accumulation of CD4 T cells in intestine using murine models of inflammatory bowel disease. We found that genetic deletion of CD69 in mice increases the expression of the chemokines CCL-1, CXCL-10 and CCL-19 in CD4(+) T cells and/or CD4(-) cells. Efficient in vitro migration of CD69-deficient CD4 T cells toward the chemokine stimuli was the result of increased expression and/or affinity of chemokine receptors. In vivo CD69(-/-) CD4 T cells accumulate in the intestine in higher numbers than B6 CD4 T cells as observed in competitive homing assay, dextran sodium sulphate (DSS)-induced colitis and antigen-specific transfer colitis. In DSS colitis CD69(-/-) CD4 T cell accumulation in colonic lamina propria (cLP) was associated with increased expression of CCL-1, CXCL-10 and CCL-19 genes. Furthermore, treatment of DSS-administrated CD69(-/-) mice with the mixture of CCL-1, CXCL-10 and CCL-19 neutralizing Abs significantly decreased the histopathological signs of colitis. Transfer of OT-II×CD69(-/-) CD45RB(high) CD4 T cells into RAG(-/-) hosts induced CD4 T cell accumulation in cLP. This study showed CD69 as negative regulator of inflammatory responses in intestine as it decreases the expression of chemotactic receptors and ligands and reduces the accumulation of CD4 T cells in cLP during colitis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / genetics
  • Antigens, CD / metabolism*
  • Antigens, Differentiation, T-Lymphocyte / genetics
  • Antigens, Differentiation, T-Lymphocyte / metabolism*
  • CD4-Positive T-Lymphocytes / immunology*
  • Chemokine CCL1
  • Chemokine CCL19
  • Chemokine CXCL10
  • Chemokines / immunology*
  • Colitis, Ulcerative / chemically induced
  • Colitis, Ulcerative / immunology*
  • Colitis, Ulcerative / metabolism
  • Dextran Sulfate / toxicity
  • Enzyme-Linked Immunosorbent Assay
  • Intestinal Mucosa / metabolism
  • Intestines / immunology*
  • Lectins, C-Type / genetics
  • Lectins, C-Type / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microarray Analysis
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Statistics, Nonparametric

Substances

  • Antigens, CD
  • Antigens, Differentiation, T-Lymphocyte
  • CD69 antigen
  • Chemokine CCL1
  • Chemokine CCL19
  • Chemokine CXCL10
  • Chemokines
  • Lectins, C-Type
  • Dextran Sulfate

Grant support

This work was supported by grants Ni575/6-2 and Ni575/7-1 from the Deutsche Forschungsgemeinschaft (DFG) to J.H.N., the International Graduate School of Molecular Medicine of Ulm University (GSC270) to V.R. and a young investigator travel awards to K.R. by the European Mucosal Immunology Group (EMIG) and by the German Gastroenterology Association (DGVS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.