Summary Costimulation through Junctional Adhesion Molecule-Like protein interaction with Coxsackie and Adenovirus Receptor mediates epithelial γδ T cell-specific activation and effector function during tissue repair. γδ T cells present in epithelial tissues provide a crucial first line of defence against environmental insults, including infection, trauma and malignancy, yet the molecular events surrounding their activation remain poorly defined. Here we identify an epithelial γδ T cell-specific costimulatory molecule, Junctional Adhesion Molecule-Like protein (JAML). Binding of JAML to its ligand Coxsackie and Adenovirus receptor (CAR) provides costimulation leading to cellular proliferation and cytokine and growth factor production. Inhibition of JAML costimulation leads to diminished γδ T cell activation and delayed wound closure akin to that seen in the absence of γδ T cells. Our results identify JAML as a crucial component of epithelial γδ T cell biology and have broader implications for CAR and JAML in tissue homeostasis and repair.

No abstract

γδ T cells respond rapidly to keratinocyte damage in the skin, providing essential contributions to the wound healing process, but the molecular interactions regulating their response are unknown. Here we identify a role for the interaction of plexin B2 and the CD100 receptor in epithelial repair. In vitro blocking of plexin B2 or CD100 inhibited γδ T cell activation. Furthermore, CD100 deficiency in vivo resulted in delayed repair of cutaneous wounds due to a disrupted γδ T cell response to keratinocyte damage. Direct ligation of CD100 in γδ T cells induced cellular rounding via signals through ERK kinase and cofilin. Defects in this rounding process were evident in the absence of CD100-mediated signals, thereby providing a mechanistic explanation for the defective wound healing in CD100-deficient animals. The discovery of immune functions for plexin B2 and CD100 provides insight into the complex cell-cell interactions between epithelial resident γδ T cells and the neighboring cells they support.

Gene therapy currently in development for hemoglobinopathies utilizes ex vivo lentiviral transduction of CD34 hematopoietic stem and progenitor cells (HSPCs). A small-molecule screen identified prostaglandin E (PGE) as a positive mediator of lentiviral transduction of CD34 cells. Supplementation with PGE increased lentiviral vector (LVV) transduction of CD34 cells approximately 2-fold compared to control transduction methods with no effect on cell viability. Transduction efficiency was consistently increased in primary CD34 cells from multiple normal human donors and from patients with β-thalassemia or sickle cell disease. Notably, PGE increased transduction of repopulating human HSPCs in an immune-deficient (nonobese diabetic/severe combined immunodeficiency/interleukin-2 gamma receptor null [NSG]) xenotransplantation mouse model without evidence of in vivo toxicity, lineage bias, or a de novo bias of lentiviral integration sites. These data suggest that PGE improves lentiviral transduction and increases vector copy number, therefore resulting in increased transgene expression. As a result, PGE may be useful in clinical gene therapy applications using lentivirally modified HSPCs.

Skin-resident T cells have been shown to play important roles in tissue homeostasis and wound repair, but their role in UV radiation (UVR)–mediated skin injury and subsequent tissue regeneration is less clear. In this study, we demonstrate that acute UVR rapidly activates skin-resident T cells in humans and dendritic epidermal γδ T cells (DETCs) in mice through mechanisms involving the release of ATP from keratinocytes. Following UVR, extracellular ATP leads to an increase in CD69 expression, proliferation, and IL-17 production, and to changes in DETC morphology. Furthermore, we find that the purinergic receptor P2X7 and caspase-1 are necessary for UVR-induced IL-1 production in keratinocytes, which increases IL-17 secretion by DETCs. IL-17, in turn, induces epidermal TNF-related weak inducer of apoptosis and growth arrest and DNA damage–associated gene 45, two molecules linked to the DNA repair response. Finally, we demonstrate that DETCs and human skin-resident T cells limit DNA damage in keratinocytes. Taken together, our findings establish a novel role for skin-resident T cells in the UVR-associated DNA repair response and underscore the importance of skin-resident T cells to overall skin regeneration.