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.

CD8αβ+ γδ T Cells: A Novel T Cell Subset with a Potential Role in Inflammatory Bowel Disease

“…gd T cells have previously been defined as being primarily either CD8aa + or CD8 2 (1, 2). In addition, uncommon CD4 + gd T cells have been reported (3,4). Here, we describe a subset of human gd T cells expressing the CD8ab heterodimer.…”

“…Conventional T cells express the ab variant of the TCR together with either the CD4 or CD8ab coreceptor. The unconventional T cells on the other hand have been postulated to express either the ab TCR or the gd TCR, together with the coreceptor CD8aa homodimer or no coreceptor at all (1,2), although rare CD4 + gd T cells also have been described (3,4).…”

Loss of Intra-Epithelial Endocervical Gamma Delta (GD) 1 T Cells in HIV-Infected Women

“…In contrast, majority of the small intestine intraepithelial GD T lymphocytes express homodimer CD8αα 41 . Expression of CD8 or CD4 molecules on the surface of GD cells has been associated with cytotoxic (CD8αα+ small intestine intraepithelial GD T cells highly express effector molecules like granzyme and perforin 41, 42 ) as well as immunoregulatory functions (peripheral blood CD4+GD1+ T cells are precursors of naïve αβ T cells 43 ). There were no reports regarding the expression of CD8 and CD4 on reproductive tract GD T cells, so we wanted to determine the intraepithelial endocervical phenotype in more details.…”

Isolation and <em>Ex Vivo</em> Culture of V&#948;1⁺CD4⁺&#947;&#948; T Cells, an Extrathymic &#945;&#946;T-cell Progenitor

“…11. Verify the purity of the cells by FACS analysis 18 with the same antibody panel as before (see 2.1.2) and count the cells.…”