Vγ4 γδ T Cells Provide an Early Source of IL-17A and Accelerate Skin Graft Rejection

Abstract

Activated γδ T cells have been shown to accelerate allograft rejection. However, the precise role of skin-resident γδ T cells and their subsets-Vγ5 (epidermis), Vγ1, and Vγ4 (dermis)-in skin graft rejection have not been identified. Here, using a male to female skin transplantation model, we demonstrated that Vγ4 T cells, rather than Vγ1 or Vγ5 T cells, accelerated skin graft rejection and that IL-17A was essential for Vγ4 T-cell-mediated skin graft rejection. Moreover, we found that Vγ4 T cells were required for early IL-17A production in the transplanted area, both in skin grafts and in the host epidermis around grafts. Additionally, the chemokine (C-C motif) ligand 20-chemokine receptor 6 pathway was essential for recruitment of Vγ4 T cells to the transplantation area, whereas both IL-1β and IL-23 induced IL-17A production from infiltrating cells. Lastly, Vγ4 T-cell-derived IL-17A promoted the accumulation of mature dendritic cells in draining lymph nodes to subsequently regulate αβ T-cell function after skin graft transplantation. Taken together, our data reveal that Vγ4 T cells accelerate skin graft rejection by providing an early source of IL-17A.

Interleukin‐17‐producing γδ T (γδ17) cells in inflammatory diseases

“…γδ 17 cells are also implicated in the pathogenesis of spondyloarthritis; the CD27 − γδ T‐cell population is increased in the Achilles tendon after over‐expression of IL‐23, which induces spondyloarthritis‐like enthesitis in mice 65. The V γ 4 + subset produces IL‐17 in the skin grafts and in the host epidermis around grafts, suggesting the involvement in skin graft rejection 66. V γ 4 + cell‐derived IL‐17 promotes the accumulation of mature dendritic cells in the draining lymph nodes to subsequently increase Th17 cells after skin graft transplantation 66…”

“…65 The Vc4 + subset produces IL-17 in the skin grafts and in the host epidermis around grafts, suggesting the involvement in skin graft rejection. 66 Vc4 + cell-derived IL-17 promotes the accumulation of mature dendritic cells in the draining lymph nodes to subsequently increase Th17 cells after skin graft transplantation. 66…”

“…66 Vc4 + cell-derived IL-17 promotes the accumulation of mature dendritic cells in the draining lymph nodes to subsequently increase Th17 cells after skin graft transplantation. 66…”

IL-15 Enhances Activation and IGF-1 Production of Dendritic Epidermal T Cells to Promote Wound Healing in Diabetic Mice

“…In addition, impaired inflammation has been demonstrated to contribute to defective diabetic wound healing ( 37 ). Vγ4 T cells as major source of IL-17A played critical role in skin inflammation at early stage of skin injury ( 38 ). Application of Vγ4 T cells onto wound bed promoted wound healing of STZ-induced diabetic mice ( 39 ).…”

The complex existence of γδ T cells following transplantation: the good, the bad and the simply confusing

“…However, the proposed mechanisms differ between the studies, with γδ T cells either inducing the recruitment αβ T cells into the allograft, or alternatively by inducing neutrophil recruitment through the production of IL‐17 . The production of IL‐17 from γδ T cells also is reported to contribute to acute and chronic allograft dysfunction in small animal models of skin, heart and lung transplantation. However, in the mouse model of lung transplantation, despite being potent producers of intragraft IL‐17, there was no effect of γδ T cell depletion on the development of acute rejection or fibrosis .…”