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Bone Marrow-Derived Hemopoietic Precursors Commit to the T Cell Lineage Only after Arrival in the Thymic Microenvironment¹

Kornelia Heinzel^*, Claudia Benz^*, Vera C. Martins^*, Ian D. Haidl and Conrad C. Bleul^2,*

^* Department of Developmental Immunology, Max-Planck-Institute for Immunobiology, Freiburg, Germany; and Department of Pediatrics and Department of Microbiology and Immunology, IWK Health Centre, Halifax Nova Scotia, Canada

T lymphocytes develop in the thymus from hemopoietic precursors that commit to the T cell lineage under the influence of Notch signals. In this study, we show by single cell analyses that the most immature hemopoietic precursors in the adult mouse thymus are uncommitted and specify to the T cell lineage only after their arrival in the thymus. These precursors express high levels of surface Notch receptors and rapidly lose B cell potential upon the provision of Notch signals. Using a novel culture system with complexed, soluble Notch ligands that allows the titration of T cell lineage commitment, we find that these precursors are highly sensitive to both Delta and Jagged ligands. In contrast, their phenotypical and functional counterparts in the bone marrow are resistant to Notch signals that efficiently induce T cell lineage commitment in thymic precursors. Mechanistically, this is not due to differences in receptor expression, because early T lineage precursors, bone marrow lineage marker-negative, Sca-1-positive, c-Kit-positive and common lymphoid progenitor cells, express comparable amounts of surface Notch receptors. Our data demonstrate that the sensitivity to Notch-mediated T lineage commitment is stage-dependent and argue against the bone marrow as the site of T cell lineage commitment.

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 project was supported by Deutsche Forschungsgemeinschaft Grant SFB620/A7. V.C.M. was supported by a grant from the Fundação para a Ciência e a Tecnologia.

² Address correspondence and reprint requests to Dr. Conrad C. Bleul, Max-Planck-Institute for Immunobiology; Department of Developmental Immunology, Stübeweg 51, 79108 Freiburg, Germany. E-mail address: bleul{at}immunbio.mpg.de

³ Abbreviations used in this paper: ETP, early T lineage progenitor; CLP, common lymphoid progenitor; DN, double negative; EGFP, enhanced GFP; hFc, human Fc; Lin, lineage marker; mFc, mouse Fc; SCF, stem cell factor; TMP, thymic multipotent precursor; TN, triple negative.

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