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* Department of Dermatology, Brigham and Women’s Hospital, Boston, MA 02115;
Departments of Dermatology and Pathology, Harvard Medical School, Boston, MA 02115;
Centre d’Immunologie de Marseille-Luminy, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de la Mediterranée, Campus de Luminy, Marseille, France; and
Cytokines et Développement Lymphoïde, INSERM Unité 668, Institute Pasteur, Paris, France
CCL25 and CCR9 constitute a chemokine/receptor pair involved in T cell development and in gut-associated immune responses. In this study, we generated CCL25–/– mice to answer questions that could not be addressed with existing CCR9–/– mice. Similar phenotypes were observed for both CCL25–/– and CCR9–/– mice, consistent with the notion that CCL25 and CCR9 interact with each other exclusively. We assessed the requirement for CCL25 in generating CCR9high CD8 intestinal memory-phenotype T cells and the subsequent accumulation of these cells within effector sites. TCR-transgenic naive CD8 T cells were transferred into wild-type or CCL25-deficient hosts. Oral sensitization with Ag allowed these naive donor cells to efficiently differentiate into CCR9high memory-phenotype cells within the mesenteric lymph nodes of wild-type hosts. This differentiation event occurred with equal efficiency in the MLN of CCL25-deficient hosts, demonstrating that CCL25 is not required to induce the CCR9high memory phenotype in vivo. However, we found that CCL25 deficiency severely impaired the Ag-dependent accumulation of donor-derived CD8 T cells within both lamina propria and epithelium of the small intestine. Thus, although CCL25 is not necessary for generating memory-phenotype CD8 T cells with "gut-homing" properties, this chemokine is indispensable for their trafficking to the small intestine.
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1 This work was supported by R01-AI046784 from the National Institutes of Health National Institute of Allergy and Infectious Diseases (to J.J.C.) and a research award from the Crohn’s and Colitis Foundation of America (to M.-A.W.). The generation and preliminary characterization of CCL25-deficient mice was performed by M.-A.W. in the laboratory of M.M. and B.M. and was supported by Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, the European Communities (MUGEN Network of Excellence), Fondation pour la Recherche Médicale (Défis de la Recherche en Allergie), and the RIO/MNG Platform.
2 Address correspondence and reprint requests to Dr. James J. Campbell, Department of Dermatology, Brigham and Women’s Hospital, 221 Longwood Avenue, Eugene Braunwald Research Center 511, Boston, MA 02115; E-mail address: jcampbell{at}rics.bwh.harvard.edu or Dr. Bernard Malissen, Centre d’Immunologie de Marseille-Luminy, Parc Scientifique et Technologique de Luminy, Case 906, 13009 Marseille Cedex 09, France; E-mail address: bernardm{at}ciml.univ-mrs.fr (address requests for CCL25-deficient mice to Dr. B. Malissen).
3 Abbreviations used in this paper: BM, bone marrow; WT, wild type; SPF, specific pathogen free; Tg, transgenic; ES, embryonic stem; SPL, spleen; MLN, mesenteric lymph node; PLN, peripheral lymph node; PP, Peyer’s patch; LP, lamina propria; LPL, LP lymphocyte; IEL, intraepithelial lymphocyte; CT, cholera toxin; DN, double negative; DP, double positive; SP, single positive; EC, epithelial cell; GALT, gut-associated lymphoid tissue.
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