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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+CD[38.sup.dim]Lin- cells, which resemble multipotent progenitors in the bone marrow and thymus; (b) more mature CD34+CD[38.sup.bright]Lin- 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., Introduction The development of human T cells can be divided into discrete stages, ranging from that for multipotent progenitors to that for naive T cells. The expression of CD4 and/or [...]