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
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
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Research Article Immunology Transplantation

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

Abstract

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.

Authors

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

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Figure 5

T cell progenitors without T cell–competent BM stimulate temporary medullary thymic epithelial cell recovery.

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T cell progenitors without T cell–competent BM stimulate temporary medul...
Lethally irradiated CD45.1 B6 recipients were given CD45.2 Rag-/- BM with or without Thy1.1 progenitors (proTs). Thymi were harvested at the indicated time points, and their thymic epithelial cells were analyzed by flow cytometry. Data are representative of 3 separate experiments, with 3–5 animals per group per time point. Data are shown as mean ± SEM. Data sets were compared using 2-way ANOVA. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, ****P ≤ 0.0001. (A) Numbers of thymic epithelial cells expressed as a percentage of a non-BMT controls at the indicated time points. (B) Numbers of BrdU+ thymic epithelial cells expressed as a percentage of a non-BMT controls at the indicated time points. (C) Absolute numbers of medullary thymic epithelial cells at day 21 after transplant. (D) Absolute numbers of cortical thymic epithelial cells at day 21 after transplant. (E) UEA-1 (red) and BP-1 (green) staining of thymic sections at day 21 of nontransplanted controls. (F) Rag-/- BM recipients and (G) recipients of Rag-/- BM and proTs. Original magnification, ×10. (H) Quantification of UEA-1 immunofluorescent signal.