title: Human Peripheral CD4(+) Vδ1(+) γδT Cells Can Develop into αβT Cells.
abstract: The lifelong generation of αβT cells enables us to continuously build immunity against pathogens and malignancies despite the loss of thymic function with age. Homeostatic proliferation of post-thymic naïve and memory T cells and their transition into effector and long-lived memory cells balance the decreasing output of naïve T cells, and recent research suggests that also αβT-cell development independent from the thymus may occur. However, the sites and mechanisms of extrathymic T-cell development are not yet understood in detail. γδT cells represent a small fraction of the overall T-cell pool, and are endowed with tremendous phenotypic and functional plasticity. γδT cells that express the Vδ1 gene segment are a minor population in human peripheral blood but predominate in epithelial (and inflamed) tissues. Here, we characterize a CD4(+) peripheral Vδ1(+) γδT-cell subpopulation that expresses stem-cell and progenitor markers and is able to develop into functional αβT cells ex vivo in a simple culture system and in vivo. The route taken by this process resembles thymic T-cell development. However, it involves the re-organization of the Vδ1(+) γδTCR into the αβTCR as a consequence of TCR-γ chain downregulation and the expression of surface Vδ1(+)Vβ(+) TCR components, which we believe function as surrogate pre-TCR. This transdifferentiation process is readily detectable in vivo in inflamed tissue. Our study provides a conceptual framework for extrathymic T-cell development and opens up a new vista in immunology that requires adaptive immune responses in infection, autoimmunity, and cancer to be reconsidered.
authors.affiliation: Department of Hematology and Oncology, University Children's Hospital, University of Tübingen , Tübingen , Germany.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Ziegler
authors.affiliation: Department of Hematology and Oncology, University Children's Hospital, University of Tübingen , Tübingen , Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Welker
authors.affiliation: Department of Hematology and Oncology, University Children's Hospital, University of Tübingen , Tübingen , Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Sterk
authors.affiliation: Department of Hematology and Oncology, University Children's Hospital, University of Tübingen , Tübingen , Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Haarer
authors.affiliation: Department of Immunology, Interfaculty Institute for Cell Biology, University of Tübingen , Tübingen , Germany.
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Rammensee
authors.affiliation: Department of Hematology and Oncology, University Children's Hospital, University of Tübingen , Tübingen , Germany.
authors.forename: Rupert
authors.initials: R
authors.lastname: Handgretinger
authors.affiliation: Department of Hematology and Oncology, University Children's Hospital, University of Tübingen , Tübingen , Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Schilbach
keywords: T-cell development; Vδ1+ γδT cells; extrathymic T-cell development; extrathymic T-cell progenitor; hematopoietic progenitor cell; inflammation; δβ heterodimer