Journal of Leukocyte Biology
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Originally published online as doi:10.1189/jlb.0607423 on October 2, 2007

Published online before print October 2, 2007
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(Journal of Leukocyte Biology. 2008;83:156-164.)
© 2008 by Society for Leukocyte Biology

Involvement of CCR9 at multiple stages of adult T lymphopoiesis

Marcus Svensson*,1, Jan Marsal*,1, Heli Uronen-Hansson*, Min Cheng{dagger}, William Jenkinson{ddagger}, Corrado Cilio§, Sten Eirik W. Jacobsen{dagger}, Ewa Sitnicka{dagger}, Graham Anderson{ddagger} and William W. Agace*,2

* Immunology Section, Lund University, and
{dagger} Hematopoietic Stem Cell Laboratory, Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, Lund University Hospital, Lund, Sweden;
§ Department of Clinical Sciences and Department of Pediatrics, Cellular Autoimmunity Unit, Malmö University Hospital, Malmö, Sweden; and
{ddagger} MRC Centre for Immune Regulation, Institute of Biomedical Research, University of Birmingham, Birmingham, United Kingdom

2 Correspondence: Immunology Section, Lund University, BMCI13, Lund, Sweden. E-mail: william.agace{at}med.lu.se

The chemokine CCL25 is constitutively expressed in the thymus, and its receptor CCR9 is expressed on subsets of developing thymocytes. Nevertheless, the function of CCL25/CCR9 in adult thymopoiesis remains unclear. Here, we demonstrate that purified CCR9–/– hematopoietic stem cells are deficient in their ability to generate all major thymocyte subsets including double-negative 1 (DN1) cells in competitive transfers. CCR9–/– bone marrow contained normal numbers of lineage– Sca-1+c-kit+, common lymphoid progenitors, and lymphoid-primed multipotent progenitors (LMPP), and CCR9–/– LMPP showed similar T cell potential as their wild-type (WT) counterparts when cultured on OP9–{delta}-like 1 stromal cells. In contrast, early thymic progenitor and DN2 thymocyte numbers were reduced in the thymus of adult CCR9–/– mice. In fetal thymic organ cultures (FTOC), CCR9–/– DN1 cells were as efficient as WT DN1 cells in generating double-positive (DP) thymocytes; however, under competitive FTOC, CCR9–/– DP cell numbers were reduced significantly. Similarly, following intrathymic injection into sublethally irradiated recipients, CCR9–/– DN cells were out-competed by WT DN cells in generating DP thymocytes. Finally, in competitive reaggregation thymic organ cultures, CCR9–/– preselection DP thymocytes were disadvantaged significantly in their ability to generate CD4 single-positive (SP) thymocytes, a finding that correlated with a reduced ability to form TCR-MHC-dependent conjugates with thymic epithelial cells. Together, these results highlight a role for CCR9 at several stages of adult thymopoiesis: in hematopoietic progenitor seeding of the thymus, in the DN-DP thymocyte transition, and in the generation of CD4 SP thymocytes.

Key Words: chemokines • thymus seeding • T cell development






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