ABSTRACT
CCR6 expression in dendritic, T, and B cells suggests that this beta-chemokine receptor may regulate the migration and recruitment of antigen-presenting and immunocompetent cells during inflammatory and immunological responses. Here we demonstrate that CCR6-/- mice have underdeveloped Peyer's patches, in which the myeloid CD11b+ CD11c+ dendritic-cell subset is not present in the subepithelial dome. CCR6-/- mice also have increased numbers in T-cell subpopulations within the intestinal mucosa. In 2,4-dinitrofluorobenzene-induced contact hypersensitivity (CHS) studies, CCR6-/- mice developed more severe and more persistent inflammation than wild-type (WT) animals. Conversely, in a delayed-type hypersensitivity (DTH) model induced with allogeneic splenocytes, CCR6-/- mice developed no inflammatory response. The altered responses seen in the CHS and DTH assays suggest the existence of a defect in the activation and/or migration of the CD4(+) T-cell subsets that downregulate or elicit the inflammation response, respectively. These findings underscore the role of CCR6 in cutaneous and intestinal immunity and the utility of CCR6-/- mice as a model to study pathologies in these tissues. This article was published online in advance of the print edition. The date of publication is available from the JCI website, http://www.jci.org.
Subject(s)
Dermatitis, Contact/genetics , Dermatitis, Contact/immunology , Hypersensitivity, Delayed/genetics , Hypersensitivity, Delayed/immunology , Leukocytes/immunology , Receptors, Chemokine/deficiency , Animals , CD4-Positive T-Lymphocytes/immunology , Cell Movement , Female , Homeostasis , Intestinal Mucosa/immunology , Intestinal Mucosa/pathology , Langerhans Cells/immunology , Leukocytes/pathology , Lymphocyte Activation , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Peyer's Patches/immunology , Peyer's Patches/pathology , Receptors, CCR6 , Receptors, Chemokine/genetics , Receptors, Chemokine/physiologyABSTRACT
Chemokines appear to have an important role in the seeding of lymphoid progenitors in the thymus, the regulation of the coordinated movements of the maturing T cells within this organ, and the egress of the resulting naive T cells to secondary lymphoid organs. CCR9, the specific receptor for the beta-chemokine TECK/CCL25, is selectively expressed in thymus, lymph node, and spleen. Using a specific anti-CCR9 polyclonal antibody, K629, and a semiquantitative reverse transcriptase-polymerase chain reaction procedure, a detailed study of CCR9 expression in the thymus and secondary lymphoid organs was performed. The results show that CD4(+)CD8(+) double-positive thymocytes have the highest CCR9 expression in thymus. Single-positive CD8(+) thymocytes continue to express this receptor after abandoning the thymus as mature naive T cells, as suggested by the existence of a CD8(+)CD69(low)CD62L(high) CCR9(+) cell subset. Consistent with this, CD8(+) lymphocytes from lymph nodes, spleen, and Peyer patches express a functional CCR9, as its expression correlates with migration in response to CCL25. Conversely, CD4(+) thymocytes lose CCR9 before abandoning the thymus, and CD4(+) T cells from secondary lymphoid organs also lack CCR9 expression. Analysis of CCR9 expression in thymocytes from mice of different ages showed that CCR9 levels are affected by age, as this receptor is more abundant, and its response to CCL25 is more potent in newborn animals. Collectively, these results suggest that CCR9 has a role in thymocyte development throughout murine life, with clear differences between the CD4(+) and CD8(+) lineages.
