title: 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.affiliation: Medical Scientist Training Program, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: McClory
authors.forename: Tiffany
authors.initials: T
authors.lastname: Hughes
authors.forename: Aharon G
authors.initials: AG
authors.lastname: Freud
authors.forename: Edward L
authors.initials: EL
authors.lastname: Briercheck
authors.forename: Chelsea
authors.initials: C
authors.lastname: Martin
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Trimboli
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yu
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Zhang
authors.forename: Gustavo
authors.initials: G
authors.lastname: Leone
authors.forename: Gerard
authors.initials: G
authors.lastname: Nuovo
authors.forename: Michael A
authors.initials: MA
authors.lastname: Caligiuri
mesh_terms: D015703:Antigens, CD / Q000032:analysis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis; D019070:Cell Lineage; D006412:Hematopoietic Stem Cells / Q000737:chemistry / Q000166:cytology; D018398:Homeodomain Proteins / Q000032:analysis; D006801:Humans; D016130:Immunophenotyping; D007694:Killer Cells, Natural / Q000737:chemistry / Q000166:cytology*; D038041:Lymphopoiesis; D008562:Membrane Glycoproteins / Q000032:analysis; D009928:Organ Specificity; D014066:Palatine Tonsil / Q000166:cytology / Q000276:immunology* / Q000648:ultrastructure; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000032:analysis; D055153:Stem Cell Niche; D016176:T-Lymphocyte Subsets / Q000737:chemistry / Q000166:cytology*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D018398:Homeodomain Proteins; D008562:Membrane Glycoproteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; C090377:pre-T cell receptor alpha; C064658:RAG-1 protein