title: Pre-differentiated human committed T-lymphoid progenitors promote peripheral T-cell re-constitution after stem cell transplantation in immunodeficient mice.
abstract: T-cell re-constitution after allogeneic stem cell transplantation (alloSCT) is often dampened by the slow differentiation of human peripheral blood CD34(+)  (huCD34(+) ) hematopoietic stem cells (HSCs) into mature T cells. This process may be accelerated by the co-transfer of in vitro-pre-differentiated committed T/NK-lymphoid progenitors (CTLPs). Here, we analysed the developmental potential of huCD34(+)  HSCs compared with CTLPs from a third-party donor in a murine NOD-scid IL2Rγ(null)  model of humanised chimeric haematopoiesis. CTLPs (CD34(+) lin(-) CD45RA(+) CD7(+) ) could be generated in vitro within 10 days upon co-culture of huCD34(+)  or cord blood CD34(+)  (CB-CD34) HSCs on murine OP9/N-DLL-1 stroma cells but not in a novel 3-D cell-culture matrix with DLL-1(low)  human stroma cells. In both in vitro systems, huCD34(+)  and CB-CD34(+)  HSCs did not give rise to mature T cells. Upon transfer into 6-wk-old immune-deficient mice, CTLPs alone did not engraft. However, transplantation of CTLPs together with huCD34(+)  HSCs resulted in rapid T-cell engraftment in spleen, bone marrow and thymus at day 28. Strikingly, at this early time point mature T cells originated exclusively from CTLPs, whereas descendants of huCD34(+)  HSCs still expressed a T-cell-precursor phenotype (CD7(+) CD5(+) CD1a(+/-) ). This strategy to enhance early T-cell re-constitution with ex vivo-pre-differentiated T-lymphoid progenitors could bridge the gap until full T-cell recovery in severely immunocompromised patients after allogeneic stem cell transplantation.
authors.affiliation: Stem Cell Laboratory, University Children's Hospital Würzburg, Würzburg, Germany. Eyrich_m@klinik.uni-wuerzburg.de
authors.forename: Matthias
authors.initials: M
authors.lastname: Eyrich
authors.forename: Susanne C
authors.initials: SC
authors.lastname: Schreiber
authors.forename: Gernot
authors.initials: G
authors.lastname: Wollny
authors.forename: Hendrik
authors.initials: H
authors.lastname: Ziegler
authors.forename: Ramona
authors.initials: R
authors.lastname: Schlenker
authors.forename: Katharina
authors.initials: K
authors.lastname: Koch-Büttner
authors.forename: Matthias
authors.initials: M
authors.lastname: Wölfl
authors.forename: Paul G
authors.initials: PG
authors.lastname: Schlegel
authors.forename: Karin
authors.initials: K
authors.lastname: Schilbach
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D005312:Fetal Blood / Q000276:immunology; D006410:Hematopoiesis / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D054503:Lymphoid Progenitor Cells / Q000166:cytology / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D017154:Stromal Cells / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*