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−/− CD45RBhigh 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.
Highlights
In the intestinal immune system chemokine ligands and receptors regulate the migration of lymphocytes
Activation of CD69 significantly reduced the expression of XCL-1, CCL-4, CCL-1, CCL-9, CCL-3, CXCL-9 and CXCL-10 chemokine and CCR-8, CCR-4, CCR-5 chemokine receptor transcripts in B6 CD4 T cells as compared to CD692/2 CD4 T cells (Table 1)
In absence of CD69 an increased expression of CCL-1, CXCL-10 and CCL-19 genes was observed in mesenteric lymph nodes (MLN), small intestinal and colonic tissues (Fig. 1A–C)
Summary
In the intestinal immune system chemokine ligands and receptors regulate the migration of lymphocytes. Naıve cells express high levels of L-selectin (CD62L) and chemokine receptor CCR-7 that recognize secondary lymphoid organs (SLO)expressed addressin and the chemokines CCL-19 and CCL-21, respectively [1,2,3]. Lymphocyte egress from the SLO depends on the expression of sphingosine 1-phosphate receptor type 1 (S1P1) on the lymphocyte surface and its interaction with the ligand sphingosine 1-phosphate (S1P) that is abundant in the lymph [4,5]. Activated lymphocytes express different combinations of chemokine receptors depending on their migration destination and the subtype they differentiate to. Lymphocytes that migrate from the SLO to the gut express the chemokine receptor CCR-9 and the integrin a4b7 that bind CCL-25 and mucosal addressin cell adhesion mlecule-1 (MadCAM-1), respectively [1,2]
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