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* Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104;
Division of Hematology-Oncology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; and
Laboratory of Mammalian Genes and Development, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892
To generate T cells throughout adult life, the thymus must import hemopoietic progenitors from the bone marrow via the blood. In this study, we establish that thymus settling is selective. Using nonirradiated recipient mice, we found that hemopoietic stem cells were excluded from the thymus, whereas downstream multipotent progenitors (MPP) and common lymphoid progenitors rapidly generated T cells following i.v. transfer. This cellular specificity correlated with the expression of the chemokine receptor CCR9 by a subset of MPP and common lymphoid progenitors but not hemopoietic stem cells. Furthermore, CCR9 expression was required for efficient thymus settling. Finally, we demonstrate that a prethymic signal through the cytokine receptor fms-like tyrosine kinase receptor-3 was required for the generation of CCR9-expressing early lymphoid progenitors, which were the most efficient progenitors of T cells within the MPP population. We conclude that fms-like tyrosine kinase receptor-3 signaling is required for the generation of T lineage-competent progenitors, which selectively express molecules, including CCR9, that allow them to settle within the thymus.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the National Institutes of Health Grants AI059621 (to A.B.) and T32-AI-055428 (to B.A.S.) and Damon Runyon Cancer Research Foundation Grant DRG-102-05 (to I.M.). A.B. is the recipient of a Career Development Award from the Leukemia and Lymphoma Society.
2 B.A.S. and A.S. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Avinash Bhandoola, Department of Pathology and Laboratory Medicine, 264/266 John Morgan Building, 37th and Hamilton Walk, University of Pennsylvania School of Medicine, Philadelphia, PA 19104. E-mail address: bhandooa{at}mail.med.upenn.edu
4 Abbreviations used in this paper: BM, bone marrow; CLP, common lymphoid progenitor; DN, CD4–CD8– double negative; DP, CD4+CD8+ double positive; ELP, early lymphoid progenitor; ETP, early T lineage progenitor; Flt3, fms-like tyrosine kinase receptor-3; Flt3L, Flt3 ligand; HSC, hemopoietic stem cell; Lin, lineage Ag; MPP, multipotent progenitor; Sca-1, stem cell Ag-1; WT, wild type; LSK, Lin–Sca-1highc-Kithigh.
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