Extrathymic development of murine T cells after bone marrow transplantation
Amanda M. Holland, … , Joseph C. Sun, Marcel R.M. van den Brink
Amanda M. Holland, … , Joseph C. Sun, Marcel R.M. van den Brink
Published November 19, 2012
Citation Information: J Clin Invest. 2012;122(12):4716-4726. https://doi.org/10.1172/JCI60630.
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Extrathymic development of murine T cells after bone marrow transplantation

Abstract

Restoring T cell competence is a significant clinical challenge in patients whose thymic function is severely compromised due to age or cytoreductive conditioning. Here, we demonstrate in mice that mesenteric LNs (MLNs) support extrathymic T cell development in euthymic and athymic recipients of bone marrow transplantation (BMT). Furthermore, in aged murine BMT recipients, the contribution of the MLNs to the generation of T cells was maintained, while the contribution of the thymus was significantly impaired. Thymic impairment resulted in a proportional increase in extrathymic-derived T cell progenitors. Extrathymic development in athymic recipients generated conventional naive TCRαβ T cells with a broad Vβ repertoire and intact functional and proliferative potential. Moreover, in the absence of a functional thymus, immunity against known pathogens could be augmented using engineered precursor T cells with viral specificity. These findings demonstrate the potential of extrathymic T cell development for T cell reconstitution in patients with limited thymic function.

Authors

Amanda M. Holland, Johannes L. Zakrzewski, Jennifer J. Tsai, Alan M. Hanash, Jarrod A. Dudakov, Odette M. Smith, Mallory L. West, Natalie V. Singer, Jessie Brill, Joseph C. Sun, Marcel R.M. van den Brink

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Figure 3

Extrathymic progenitors undergo NFAT signaling, engraft directly in extrathymic sites, and require PSGL-1 for repopulation.

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Extrathymic progenitors undergo NFAT signaling, engraft directly in extr...
(A–D) BLI of BALB/c→BALB/c WT or nude+NFAT vector+CD45.1+ preTs. n = 5 mice per group, combined from 2 experiments. Pseudocolor overlay represents NFAT activation. Circular regions measure thoracic signal, and rectangular regions measure abdominal signal. (B) Thoracic and abdominal signals from A. Black, WT; red, nude. (C) Representative ex vivo abdominal images at day 16 from A. (D) Representative plots of preT-derived CD4+CD8+ cells in MLNs at day 16 from A. (E) CD45.1+ B6 preT engraftment 18 hours after transfer into lethally irradiated CD45.2+ B6 WT (black, n = 10) or nude recipients (white, n = 6). Data combined from 2–3 experiments. (F) DN2 CD45.1+ B6 preTs at day 21 of culture (n = 5) with freshly isolated B6 DN2 thymocytes (n = 3 preparations). Heavy red line, DN2 preTs; heavy blue line, thymic DN2; thin red line, isotype on preTs; thin blue line, isotype on thymic DN2. (G) Competitive reconstitution at day 14 after CD45.1+CD45.2+ B6→CD45.1+CD45.2+ B6 BMT. CD4+CD8+ cells in thymus and MLNs of recipients of CD45.1+ (red) preTs and CD45.2+ (white) B6 (n = 10–12), Ccr9 KO (n = 7), or Selplg KO (n = 16) preTs. Combined from 3 to 4 experiments. **P < 0.01; ***P < 0.001.