Abstract
Thymocytes expressing the invariant Vγ5 γδT-cell receptor represent progenitors of dendritic epidermal T-cells (DETC) that play an important immune surveillance role in the skin. In contrast to the bulk of αβT-cell development, Vγ5+ DETC progenitor development occurs exclusively in fetal thymus. Whilst αβT-cell development is known to require chemokine receptor mediated migration through distinct thymus regions, culminating in medullary entry and thymic egress, the importance and control of intrathymic migration for DETC progenitors is unclear. We recently revealed a link between Vγ5+ DETC progenitor development and medullary thymic epithelial cells expressing Aire, a known regulator of thymic chemokine expression, demonstrating that normal Vγ5+ DETC progenitor development requires regulated intramedullary positioning. Here we investigate the role of chemokines and their receptors during intrathymic Vγ5+ DETC progenitor development and establishment of the DETC pool in the skin. We report that thymic medullary accumulation of Vγ5+ DETC progenitors is a G-protein coupled receptor dependent process. However, this process occurs independently of Aire’s influences on intrathymic chemokines, and in the absence of CCR4 and CCR7 expression by DETC progenitors. In contrast, analysis of epidermal γδT-cells at neonatal and adult stages in CCR4−/− mice reveals that reduced numbers of DETC in adult epidermis are not a consequence of diminished intrathymic embryonic development, nor deficiencies in initial epidermal seeding in the neonate. Collectively, our data reveal differences in the chemokine receptor requirements for intrathymic migration of αβ and invariant γδT-cells, and highlight a differential role for CCR4 in the maintenance, but not initial seeding, of DETC in the epidermis.
Highlights
During the postnatal and adult periods, most T-cells produced in the thymus express the ab form of T-cell receptor complex, and are generated via a process involving random recombination at the Tcra and Tcrb gene loci to generate a pool of immature abTCR+ thymocytes with a wide range of antigen specificities [1]
The development of Vc5+ dendritic epidermal T-cells (DETC) progenitors in the thymus begins during embryonic life, and involves the clustering of Vc5+ thymocytes with Skint-1+mTEC, an association that is evident by E17 of gestation
To investigate the mechanism influencing the recruitment of Vc5+ DETC progenitors to the embryonic thymic medulla, we performed short-term treatment of E14 fetal thymus organ cultures (FTOC) with Pertussis Toxin (PTX) (Figure 1A), a known inhibitor of
Summary
During the postnatal and adult periods, most T-cells produced in the thymus express the ab form of T-cell receptor (abTCR) complex, and are generated via a process involving random recombination at the Tcra and Tcrb gene loci to generate a pool of immature abTCR+ thymocytes with a wide range of antigen specificities [1]. Such cells are required to undergo stringent selection events based upon their ability to recognize self-peptide/ MHC ligands expressed by thymic epithelial cells and dendritic cells. Intrathymic expression of some chemokines are either absent (XCL1), reduced (CCL17, CCL19, CCL21, CCL22) or increased (CCL25) in the absence of Aire, a gene expressed by mTEC that plays a key role in regulating availability of Tissue Restricted Antigens for abT-cell tolerance induction [15,16]
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