title: Intrathymic progenitor cell transplantation across histocompatibility barriers results in the persistence of early thymic progenitors and T-cell differentiation.
abstract: Donor hematopoietic stem cells (HSCs) can correct T-cell deficiencies in patients with severe combined immunodeficiency by replacing resident thymus cells. However, as those progenitors that naturally migrate to the thymus are not capable of supporting long-term thymopoiesis, a successful transplant is thought to require the ongoing migration of donor progenitors. We previously showed that the forced intrathymic administration of histocompatible HSCs can sustain long-term thymopoiesis in ZAP-70-immunodeficient mice. However, it is not known whether T-cell reconstitution across histocompatibility barriers is modulated by intrathymic vs intravenous administration of HSCs. In the absence of conditioning, long-term thymopoiesis by semiallogeneic progenitors was detected in mice transplanted via the intrathymic, but not the intravenous, route. In intrathymic-transplanted mice, ongoing thymopoiesis was associated with a 10-fold higher level of early thymic progenitors (ETPs). The enhanced reconstitution capacity of these intrathymic-derived ETPs was corroborated by their significantly augmented myeloid lineage potential compared with endogenous ETPs. Notably, though, myeloablative conditioning resulted in a reduced expansion of intrathymic-administered donor ETPs. Thus, in the absence of conditioning, the forced thymic entry of HSCs results in a sustained T-cell development across histocompatibility barriers, highlighting the capacity of the thymus to support cells with long-term renewal potential.
authors.affiliation: Institut de Génétique Moléculaire de Montpellier, UMR5535CNRS, Université Montpellier 2, Université Montpellier 1, Montpellier, France.
authors.forename: Stéphanie C
authors.initials: SC
authors.lastname: de Barros
authors.forename: Rita
authors.initials: R
authors.lastname: Vicente
authors.forename: Karim
authors.initials: K
authors.lastname: Chebli
authors.forename: Chantal
authors.initials: C
authors.lastname: Jacquet
authors.forename: Valérie S
authors.initials: VS
authors.lastname: Zimmermann
authors.forename: Naomi
authors.initials: N
authors.lastname: Taylor
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000276:immunology*; D002478:Cells, Cultured; D006085:Graft Survival / Q000276:immunology / Q000502:physiology; D006410:Hematopoiesis / Q000276:immunology / Q000502:physiology; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006648:Histocompatibility / Q000276:immunology / Q000502:physiology*; D006650:Histocompatibility Testing; D007262:Infusions, Intravenous; D054503:Lymphoid Progenitor Cells / Q000166:cytology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D016511:Severe Combined Immunodeficiency / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000502:physiology*; D013950:Thymus Gland / Q000166:cytology; D019172:Transplantation Conditioning / Q000379:methods; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000172:deficiency / Q000235:genetics / Q000276:immunology
chemical_list: D051746:ZAP-70 Protein-Tyrosine Kinase; C497262:Zap70 protein, mouse