Human proT-cells generated in vitro facilitate hematopoietic stem cell-derived T-lymphopoiesis in vivo and restore thymic architecture.
Hematopoietic stem cell transplantation (HSCT) is followed by a period of immune deficiency due to a paucity in T-cell reconstitution. Underlying causes are a severely dysfunctional thymus and an impaired production of thymus-seeding progenitors in the host. Here, we addressed whether in vitro-derived human progenitor T (proT)-cells could not only represent a source of thymus-seeding progenitors, but also able to influence the recovery of the thymic microenvironment. We examined whether co-transplantation of in vitro-derived human proT-cells with hematopoietic stem cells (HSCs) was able to facilitate HSC-derived T-lymphopoiesis posttransplant. A competitive transfer approach was used to define the optimal proT subset capable of reconstituting immunodeficient mice. Although the 2 subsets tested (proT1, CD34(+)CD7(+)CD5(-); proT2, CD34(+)CD7(+)CD5(+)) showed thymus engrafting function, proT2-cells exhibited superior engrafting capacity. Based on this, when proT2-cells were coinjected with HSCs, a significantly improved and accelerated HSC-derived T-lymphopoiesis was observed. Furthermore, we uncovered a potential mechanism by which receptor activator of nuclear factor κb (RANK) ligand-expressing proT2-cells induce changes in both the function and architecture of the thymus microenvironment, which favors the recruitment of bone marrow-derived lymphoid progenitors. Our findings provide further support for the use of Notch-expanded progenitors in cell-based therapies to aid in the recovery of T-cells in patients undergoing HSCT.
Department of Immunology, University of Toronto, and Sunnybrook Research Institute, Toronto, ON, Canada;
Génève
G
Awong
Jastaranpreet
J
Singh
Mahmood
M
Mohtashami
Maria
M
Malm
Ross N
RN
La Motte-Mohs
Patricia M
PM
Benveniste
Pablo
P
Serra
Elaine
E
Herer
Marcel R
MR
van den Brink
Juan Carlos
JC
Zúñiga-Pflücker
D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D004195:Disease Models, Animal; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000276:immunology / Q000628:therapy*; D038041:Lymphopoiesis / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D012038:Regeneration / Q000276:immunology; D017154:Stromal Cells / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology* / Q000276:immunology