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 2

Double-negative 3 T cell progenitors stimulate mTEC recovery.

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Double-negative 3 T cell progenitors stimulate mTEC recovery. Lethally i...
Lethally irradiated CD45.1 recipients were given CD45.2 WT BM alone, with double-negative 2 (DN2) Thy1.1 progenitors (proTs) or with DN3 Thy1.1 proTs. Thymi were harvested at day 21, and their thymic epithelial cells (TECs) were analyzed by flow cytometry. Data are representative of 3 separate experiments, with 3–6 animals per group per time point. Data are shown as mean ± SEM. Data sets were compared using 2-way ANOVA. *P ≤ 0.05, ***P ≤ 0.001, ****P ≤ 0.0001. (A) Representative bulk proTs, DN2-sorted proTs, and DN3-sorted proTs. Live cells were selected, and flow cytometry plots show the DN populations of the bulk proTs (left) and DN2 proTs (middle), defined as (CD19, B220, Gr-1, CD11b, CD11c, Ter119, NK1.1)–CD45+CD4–CD8–CD25+CD44hi. DN3 proTs (right) were gated on live cells and then defined as (CD19, B220, Gr-1, CD11b, CD11c, Ter119, NK1.1)–CD45+CD4–CD8–CD25+CD44lo. (B) Absolute numbers of mTECs at day 21 after transplant. (C) Absolute numbers of cTECs at day 21 after transplant. (D) DN2 proTs or (E) DN3 proTs (Thy1.1+, blue) in the cortex (BP-1, green) and in the medulla (UEA-1, red, outlined in white) at days 7 and 21 after transplant.