title: Lymphoid Gene Upregulation on Circulating Progenitors Participates in Their T-Lineage Commitment.
abstract: Extrathymic T cell precursors can be detected in many tissues and represent an immediately competent population for rapid T cell reconstitution in the event of immunodeficiencies. Blood T cell progenitors have been detected, but their source in the bone marrow (BM) remains unclear. Prospective purification of BM-resident and circulating progenitors, together with RT-PCR single-cell analysis, was used to evaluate and compare multipotent progenitors (MPPs) and common lymphoid progenitors (CLPs). Molecular analysis of circulating progenitors in comparison with BM-resident progenitors revealed that CCR9(+) progenitors are more abundant in the blood than CCR7(+) progenitors. Second, although Flt3(-) CLPs are less common in the BM, they are abundant in the blood and have reduced Cd25(+)-expressing cells and downregulated c-Kit and IL-7Rα intensities. Third, in contrast, stage 3 MPP (MPP3) cells, the unique circulating MPP subset, have upregulated Il7r, Gata3, and Notch1 in comparison with BM-resident counterparts. Evaluation of the populations' respective abilities to generate splenic T cell precursors (Lin(-)Thy1.2(+)CD25(+)IL7Rα(+)) after grafting recipient nude mice revealed that MPP3 cells were the most effective subset (relative to CLPs). Although several lymphoid genes are expressed by MPP3 cells and Flt3(-) CLPs, the latter only give rise to B cells in the spleen, and Notch1 expression level is not modulated in the blood, as for MPP3 cells. We conclude that CLPs have reached the point where they cannot be a Notch1 target, a limiting condition on the path to T cell engagement.
authors.affiliation: INSERM, Unité 1151, Université Paris Descartes, Unité Mixte de Recherche 8253, 75993 Paris Cedex 14, France.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Zepponi
authors.affiliation: INSERM, Unité 1151, Université Paris Descartes, Unité Mixte de Recherche 8253, 75993 Paris Cedex 14, France.
authors.forename: Victoria
authors.initials: V
authors.lastname: Michaels Lopez
authors.affiliation: INSERM, Unité 1151, Université Paris Descartes, Unité Mixte de Recherche 8253, 75993 Paris Cedex 14, France.
authors.forename: Carolina
authors.initials: C
authors.lastname: Martinez-Cingolani
authors.affiliation: INSERM, Unité 1151, Université Paris Descartes, Unité Mixte de Recherche 8253, 75993 Paris Cedex 14, France.
authors.forename: Amine
authors.initials: A
authors.lastname: Boudil
authors.affiliation: INSERM, Unité 1151, Université Paris Descartes, Unité Mixte de Recherche 8253, 75993 Paris Cedex 14, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Pasqualetto
authors.affiliation: INSERM, Unité 1151, Université Paris Descartes, Unité Mixte de Recherche 8253, 75993 Paris Cedex 14, France.
authors.forename: Lamia
authors.initials: L
authors.lastname: Skhiri
authors.affiliation: INSERM, Unité 1151, Université Paris Descartes, Unité Mixte de Recherche 8253, 75993 Paris Cedex 14, France.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Gautreau
authors.affiliation: INSERM, Unité 1151, Université Paris Descartes, Unité Mixte de Recherche 8253, 75993 Paris Cedex 14, France.
authors.forename: Agnès
authors.initials: A
authors.lastname: Legrand
authors.affiliation: INSERM, Unité 1151, Université Paris Descartes, Unité Mixte de Recherche 8253, 75993 Paris Cedex 14, France.
authors.forename: Jerome
authors.initials: J
authors.lastname: Megret
authors.affiliation: INSERM, Unité 1151, Université Paris Descartes, Unité Mixte de Recherche 8253, 75993 Paris Cedex 14, France.
authors.forename: Flora
authors.initials: F
authors.lastname: Zavala
authors.affiliation: INSERM, Unité 1151, Université Paris Descartes, Unité Mixte de Recherche 8253, 75993 Paris Cedex 14, France sophie.ezine@inserm.fr.
authors.forename: Sophie
authors.initials: S
authors.lastname: Ezine
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D002454:Cell Differentiation; D019070:Cell Lineage / Q000235:genetics* / Q000276:immunology; D049109:Cell Proliferation; D005260:Female; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental / Q000276:immunology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D039902:Multipotent Stem Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000276:immunology; D051881:Receptor, Notch1 / Q000235:genetics / Q000276:immunology; D054388:Receptors, CCR / Q000235:genetics / Q000276:immunology; D054400:Receptors, CCR7 / Q000235:genetics / Q000276:immunology; D020395:Receptors, Interleukin-7 / Q000235:genetics / Q000276:immunology; D059010:Single-Cell Analysis; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D051941:fms-Like Tyrosine Kinase 3 / Q000172:deficiency / Q000235:genetics / Q000276:immunology
chemical_list: C119309:CC chemokine receptor 9; C515371:Ccr7 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D054388:Receptors, CCR; D054400:Receptors, CCR7; D020395:Receptors, Interleukin-7; C415350:interleukin-7 receptor, alpha chain; C497971:Flt3 protein, mouse; D019009:Proto-Oncogene Proteins c-kit; D051941:fms-Like Tyrosine Kinase 3