Human Peripheral CD4(+) Vδ1(+) γδT Cells Can Develop into αβT Cells.

The lifelong generation of alpha beta T cells enables us to continuously build immunity against pathogens and malignancies despite the loss of thymic function with age. Homeostatic proliferation of post-thymic naive and memory T cells and their transition into effector and long-lived memory cells balance the decreasing output of naiveT cells, and recent research suggests that also alpha beta T-cell development independent from the thymus may occur. However, the sites and mechanisms of extrathymic T-cell development are not yet understood in detail. gamma delta T cells represent a small fraction of the overall T-cell pool, and are endowed with tremendous phenotypic and functional plasticity. gamma delta T cells that express the V delta 1 gene segment are a minor population in human peripheral blood but predominate in epithelial (and inflamed) tissues. Here, we characterize a CD4(+) peripheral V delta 1(+) gamma delta T-cell subpopulation that expresses stem-cell and progenitor markers and is able to develop into functional alpha beta T 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 V delta 1(+) gamma delta TCR into the alpha beta TCR as a consequence of TCR-gamma chain downregulation and the expression of surface V delta 1(+)\/beta(+) 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 extrathymicT-cell development and opens up a new vista in immunology that requires adaptive immune responses in infection, autoimmunity, and cancer to be reconsidered.