Evidence for a stepwise program of extrathymic T cell development within the human tonsil
Susan McClory, … , Gerard Nuovo, Michael A. Caligiuri
Susan McClory, … , Gerard Nuovo, Michael A. Caligiuri
Published March 1, 2012
Citation Information: J Clin Invest. 2012;122(4):1403-1415. https://doi.org/10.1172/JCI46125.
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Research Article Immunology

Evidence for a stepwise program of extrathymic T cell development within the human tonsil

Abstract

The development of a broad repertoire of T cells, which is essential for effective immune function, occurs in the thymus. Although some data suggest that T cell development can occur extrathymically, many researchers remain skeptical that extrathymic T cell development has an important role in generating the T cell repertoire in healthy individuals. However, it may be important in the setting of poor thymic function or congenital deficit and in the context of autoimmunity, cancer, or regenerative medicine. Here, we report evidence that a stepwise program of T cell development occurs within the human tonsil. We identified 5 tonsillar T cell developmental intermediates: (a) CD34+CD38dimLin– cells, which resemble multipotent progenitors in the bone marrow and thymus; (b) more mature CD34+CD38brightLin– cells; (c) CD34+CD1a+CD11c– cells, which resemble committed T cell lineage precursors in the thymus; (d) CD34–CD1a+CD3–CD11c– cells, which resemble CD4+CD8+ double-positive T cells in the thymus; and (e) CD34–CD1a+CD3+CD11c– cells. The phenotype of each subset closely resembled that of its thymic counterpart. The last 4 populations expressed RAG1 and PTCRA, genes required for TCR rearrangement, and all 5 subsets were capable of ex vivo T cell differentiation. TdT+ cells found within the tonsillar fibrous scaffold expressed CD34 and/or CD1a, indicating that this distinct anatomic region contributes to pre–T cell development, as does the subcapsular region of the thymus. Thus, we provide evidence of a role for the human tonsil in a comprehensive program of extrathymic T cell development.

Authors

Susan McClory, Tiffany Hughes, Aharon G. Freud, Edward L. Briercheck, Chelsea Martin, Anthony J. Trimboli, Jianhua Yu, Xiaoli Zhang, Gustavo Leone, Gerard Nuovo, Michael A. Caligiuri

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Figure 8

NK cell differentiation potential of putative extrathymic T cell precursors in the human tonsil.

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NK cell differentiation potential of putative extrathymic T cell precurs...
(A) Tonsil and thymus cells were sorted as described in Figure 5A. Sorted cells were cultured on OP9-GFP cells and cultured with FL, KL, IL-3, IL-7, and IL-15 for 18 to 19 days. Harvested cells were gated on GFP–CD45+ events and analyzed for expression of CD3 and CD56. (B and C) GFP–CD45+ progeny from populations 1–4 were gated on CD3– events and analyzed for expression of CD56, CD161, NKp46, and CD5. CD3, CD56, CD161, and CD5 data are representative of independent experiments performed with 3 tonsil or 5 thymus donors. NKp46 data are representative of 2 experiments performed with tonsil donors or 3 experiments performed with thymic donors. No data (ND) are available for NKp46 or CD5 expression on progeny of thymic population 4 cells, due to the low numbers of harvested cells. All dot plots and gate frequencies are from a representative experiment. Numbers within each quadrant represent the percentage of events falling within that gate for the representative experiment shown.