Bone marrow-derived hemopoietic precursors commit to the T cell lineage only after arrival in the thymic microenvironment.
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.
Heinzel
Kornelia
K
Department of Developmental Immunology, Max-Planck-Institute for Immunobiology, Stübeweg 51, 79108 Freiburg, Germany.
Benz
Claudia
C
Martins
Vera C
VC
Haidl
Ian D
ID
Bleul
Conrad C
CC
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology; D002135:Calcium-Binding Proteins / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage / Q000276:immunology*; D002465:Cell Movement; D002478:Cells, Cultured; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000276:immunology / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008024:Ligands; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology* / Q000276:immunology*; D013997:Time Factors
D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008024:Ligands; D008565:Membrane Proteins; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; C064045:delta protein