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Published online before print October 2, 2007
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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0607423

Received for publication June 21, 2007.
Revised September 5, 2007.
Accepted for publication September 5, 2007.

Article

Involvement of CCR9 at multiple stages of adult T lymphopoiesis

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

*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; {sect}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, United Kingdom

@ To whom correspondence should be addressed. E-mail: William.Agace{at}med.lu.se.


  Abstract

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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