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.
Highlights
Hematopoietic stem-cells (HSCs) are rare, phenotypically and functionally diverse cells that can give rise to all cell lineages of the immune system [1]
We show that the rare and so far unappreciated entity of human CD4+ Vδ1+ γδT cells, isolated from the peripheral γδT-cell pool of healthy individuals, expresses markers that are characteristic of the earliest hematopoietic progenitor cells, i.e., multipotent (MPP) and common lymphoid progenitors (CLPs)
We show that CD4+ Vδ1+ γδT cells that lack thymus-homing properties but carry chemokine receptors (CCR) that direct circulating T cells to sites of inflammation, can develop into functional, mature CD4+ or CD8+ αβT cells in an inflammatory environment
Summary
Hematopoietic stem-cells (HSCs) are rare, phenotypically and functionally diverse cells that can give rise to all cell lineages of the immune system [1]. Stroma- and thymocyte-derived signals induce their T-cell lineage commitment and the cells’ differentiation into either αβ or γδT cells through well-defined stages (DN1–DN4). In humans, these stages can be recognized by the expression of CD34, CD38, and CD1a surface proteins. The pre-TCR signal drives proliferation, induces transcriptional silencing of the TCR-γ chain [4] and initiates the transition of the T cells into CD4+ and CD8+ expressing double-positive (DP) stages. In humans, this transition involves immature singlepositive (ISP) CD4+ intermediates [5]. DP T cells that recognize self-MHC class I or II molecules below an acceptable threshold of reactivity (negative selection) develop into single-positive (SP) CD4+ or CD8+ αβT cells, and are exported from the thymus into the periphery
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