T cell progenitor therapy–facilitated thymopoiesis depends upon thymic input and continued thymic microenvironment interaction

Michelle J. Smith, Dawn K. Reichenbach, Sarah L. Parker, Megan J Riddle, Jason Mitchell, Kevin C. Osum, Mahmood Mohtashami, Heather E Stefanski, Brian T Fife, Avinash Bhandoola, Kristin A Hogquist, Georg A. Holländer, Juan Carlos Zúñiga-Pflücker, Jakub Tolar, Bruce R Blazar

Research output: Contribution to journalArticlepeer-review

13 Scopus citations


Infusion of in vitro–derived T cell progenitor (proT) therapy with hematopoietic stem cell transplant aids the recovery of the thymus damaged by total body irradiation. To understand the interaction between proTs and the thymic microenvironment, WT mice were lethally irradiated and given T cell–deficient (Rag1-/-) marrow with WT in vitro–generated proTs, limiting mature T cell development to infused proTs. ProTs within the host thymus led to a significant increase in thymic epithelial cells (TECs) by day 21 after transplant, increasing actively cycling TECs. Upon thymus egress (day 28), proT TEC effects were lost, suggesting that continued signaling from proTs is required to sustain TEC cycling and cellularity. Thymocytes increased significantly by day 21, followed by a significant improvement in mature T cell numbers in the periphery by day 35. This protective surge was temporary, receding by day 60. Double-negative 2 (DN2) proTs selectively increased thymocyte number, while DN3 proTs preferentially increased TECs and T cells in the spleen that persisted at day 60. These findings highlight the importance of the interaction between proTs and TECs in the proliferation and survival of TECs and that the maturation stage of proTs has unique effects on thymopoiesis and peripheral T cell recovery.

Original languageEnglish (US)
Article numbere92056
JournalJCI Insight
Issue number10
StatePublished - May 18 2017

Bibliographical note

Funding Information:
We would like to acknowledge Patricia Taylor for her guidance and assistance in all mouse work. We would also to thank Leslie Jonart and Cordelia Dunai for their help with experiments and support. This work was supported in part by NIH grants P01 CA065493, R01 AI106791, and R01 AI081918 and Canadian Institutes of Health Research grant (MOP-119538). JCZP is supported by a Canada Research Chair in Developmental Immunology and by the Krembil Foundation.

Publisher Copyright:
© 2017 American Society for Clinical Investigation. All rights reserved.


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