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A Notch/IL-21 signaling axis primes bone marrow T cell progenitor expansion

Long-term impairment in T cell–mediated adaptive immunity is a major clinical obstacle following treatment of blood disorders with hematopoietic stem cell transplantation. Although T cell development in the thymus has been extensively characterized, there are significant gaps in our understanding of...

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Detalles Bibliográficos
Autores principales: Sottoriva, Kilian, Paik, Na Yoon, White, Zachary, Bandara, Thilinie, Shao, Lijian, Sano, Teruyuki, Pajcini, Kostandin V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9090257/
https://www.ncbi.nlm.nih.gov/pubmed/35349492
http://dx.doi.org/10.1172/jci.insight.157015
Descripción
Sumario:Long-term impairment in T cell–mediated adaptive immunity is a major clinical obstacle following treatment of blood disorders with hematopoietic stem cell transplantation. Although T cell development in the thymus has been extensively characterized, there are significant gaps in our understanding of prethymic processes that influence early T cell potential. We have uncovered a Notch/IL-21 signaling axis in bone marrow common lymphoid progenitor (CLP) cells. IL-21 receptor expression was driven by Notch activation in CLPs, and in vivo treatment with IL-21 induced Notch-dependent CLP proliferation. Taking advantage of this potentially novel signaling axis, we generated T cell progenitors ex vivo, which improved repopulation of the thymus and peripheral lymphoid organs of mice in an allogeneic transplant model. Importantly, Notch and IL-21 activation were equally effective in the priming and expansion of human cord blood cells toward the T cell fate, confirming the translational potential of the combined treatment.