Mice lacking the CCR9 CC-chemokine receptor show a mild impairment of early T- and B-cell development and a reduction in T-cell receptor γδ+ gut intraepithelial lymphocytes

Abstract

CC chemokine receptor (CCR) 9, the receptor for the CC-chemokine CCL25/ thymus-expressed chemokine (TECK), is mainly expressed by thymocytes and by intraepithelial (IEL) and lamina propria lymphocytes of the small intestine. To study the biologic role of CCR9, a mouse strain was generated in which the CCR9 gene was deleted. In spite of the high level of CCR9 found in double-and singlepositive thymocytes and of the expression of its corresponding ligand on thymic stromal cells, CCR9 deletion had no major effect on intrathymic T-cell development. It was noted that there was only a one-day lag in the appearance of doublepositive cells during fetal ontogeny in CCR9 ؊/؊ thymi. When tested in chemotaxis assay, thymocytes isolated from CCR9 ؊/؊ mice failed to respond to TECK/ CCL25. Taken together, these results suggest that in thymocytes, CCR9 is the only physiologic receptor for TECK/CCL25, and that it is dispensable for proper T-cell development. Bone marrow pre-pro-B cells migrate in response to TECK/CCL25, but more mature B cells do not. Consistent with this observation, it was shown that there are fewer pre-pro-B cells in CCR9 ؊/؊ mice than in wild-type mice. However, this diminution does not appear to have a detectable effect on the generation of a normal complement of mature B cells. Finally, it was shown that in the small intestine of CCR9-deficient mice, the intraepithelial T-cell-to-epithelial cell ratio is decreased, an observation that can be accounted for by a marked diminution of the T-cell receptor ␥␦ ؉ compartment. IntroductionDuring their development in the thymus, T cells migrate from the outer capsule to the inner medulla, a process that allows their sequential interaction with different types of stromal cells. Following their exportation to the periphery, a sophisticated network of chemokines control their appropriate navigation to and from secondary lymphoid organs. [1][2][3] Likewise, the migration of developing T and B cells within their respective primary lymphoid organs is likely under the control of chemokines. 4,5 Consistent with the implication of G protein-coupled chemokine receptors in the intrathymic trafficking of T cells, the latter is inhibited by pertussis toxin. 6 Moreover, developing thymocytes express several chemokine receptors and their corresponding ligands produced by thymic stromal cells. 7 Recent studies, including our own, have described a novel thymus-expressed chemokine (TECK)/CCL25 8,9 and its receptor, CC chemokine receptor 9 (CCR9). 9-12 TECK/CCL25 is predominantly expressed by most thymic epithelial cortical cells, by a few thymic epithelial medullary cells, and by CD11b Ϫ thymic dendritic cells. 9,13 The level of CCR9 transcripts undergoes a 10-fold increase during the double-negative (DN) to double-positive (DP) transition. Among thymocytes, DP thymocytes have the highest CCR9 expression and this correlates with their ability to migrate in response to TECK/CCL25. CCR9 transcripts subsequently decrease in single-positive (SP) thymocytes. Therefore, TECK/ CCL25 may d...

Impaired Accumulation of Antigen-Specific CD8 Lymphocytes in Chemokine CCL25-Deficient Intestinal Epithelium and Lamina Propria

“…Thymic size and cellularity were comparable among WT, CCR9 Ϫ/Ϫ , and CCL25 Ϫ/Ϫ mice. As we reported previously (6,16), there were no differences in the relative proportions of these subsets between normal and CCR9-deficient mice (Fig. 3A).…”

“…The vast majority of small-intestinal T and B lymphocytes express high levels of CCR9 (3,13). Some T cell subsets are significantly reduced within the intestinal epithelium of CCR9-deficient mice (12,16), suggesting that CCR9 is necessary for steady-state intestinal T cell development and/or gut tropism. Additionally, adoptive transfer assays demonstrate that CCR9 ϩ/ϩ lymphocytes are more efficient than CCR9 Ϫ/Ϫ lymphocytes at homing to the small intestine (17).…”

“…C57BL/6N (Charles River Laboratories), OT-1-transgenic (Tg) and B6.SJL-Ptprc a Pep3 b /BoyJ (The Jackson Laboratory) and CCL25-deficient (see below) and CCR9-deficient mice (6,16) were bred in the animal facility at the Children's Hospital (Boston, MA), and held under specific pathogen-free (SPF) conditions. All mouse procedures were approved by the Children's Hospital Institutional Animal Care and Use Committee.…”

CCR6 and NK1.1 distinguish between IL‐17A and IFN‐γ‐producing γδ effector T cells

“…2C) [28]. As expected, most GALT-derived gd T cells expressed CCR9, whereas the lowest proportion of CCR9 1 gd T cells was found in blood and spleen (Fig.…”

CCL25 induces α4β7 integrin‐dependent migration of IL‐17+γδ T lymphocytes during an allergic reaction

“…CCL25 has been acclaimed as a homeostatic chemokine that has also been shown to participate in a few inflammatory processes, mainly in the gut and oral mucosa [25,[27][28][29]. CCR9 + γδ T lymphocytes, which are present in the thymus, peripheral lymph nodes, and spleen, have been shown to be attracted by CCL25 in vitro [6,11,15].…”