Enhanced T-cell reconstitution by hematopoietic progenitors expanded ex vivo using the Notch ligand Delta1.
A physiologic role for Notch signaling in hematopoiesis has been clearly defined in lymphoid differentiation, with evidence suggesting a critical role in T-cell versus B-cell fate decisions. Previously, we demonstrated that activation of endogenous Notch receptors by culture of murine lin(-)Sca-1(+)c-kit(+) (LSK) hematopoietic progenitors with exogenously presented Notch ligand, Delta1(ext-IgG), consisting of the extracellular domain of Delta1 fused to the Fc domain of human IgG(1), promoted early T-cell differentiation and increased the number of progenitors capable of short-term lymphoid and myeloid reconstitution. Here we show that culture of LSK precursors with Delta1(ext-IgG) increases the number of progenitors that are able to rapidly repopulate the thymus and accelerate early T-cell reconstitution with a diversified T-cell receptor repertoire. Most of the early T-cell reconstitution originated from cells that expressed lymphoid-associated antigens: B220, Thy1, CD25, and/or IL7Ralpha, whereas the most efficient thymic repopulation on a per cell basis originated from the smaller number of cultured cells that did not express lymphoid-associated antigens. These findings demonstrate the potential of Delta1(ext-IgG)-cultured cells for accelerating early immune reconstitution after hematopoietic cell transplantation.
Dallas
Mari H
MH
Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N, Seattle, WA 98109, USA.
Varnum-Finney
Barbara
B
Martin
Paul J
PJ
Bernstein
Irwin D
ID
D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D007074:Immunoglobulin G / Q000235:genetics / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008565:Membrane Proteins / Q000494:pharmacology*; D051379:Mice; D017434:Protein Structure, Tertiary / Q000235:genetics; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000494:pharmacology; D020127:Recovery of Function / Q000187:drug effects*; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D018183:Transplantation Chimera / Q000378:metabolism; D014184:Transplantation, Homologous
D000943:Antigens, Differentiation; D007074:Immunoglobulin G; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008565:Membrane Proteins; D051880:Receptors, Notch; D011993:Recombinant Fusion Proteins; C064045:delta protein