Secretion of IFN-  but Not IL-17 by CD1d-Restricted NKT Cells Enhances Rejection of Skin Grafts Expressing Epithelial Cell-Derived Antigen (original) (raw)

2010, The Journal of Immunology

NKT cells are key regulators of autoimmunity, tumor immune surveillance, and the immune response to pathogens. The role of NKT cells in regulating adaptive immunity to cutaneous Ags is largely unknown. This study explores the role of CD1d-restricted NKT cells in cross-priming of CD8 effector T cells to OVA expressed in epithelial keratinocytes (K5mOVA transgenic mouse). In a skin grafting model, we show that NKT cells enhance the rejection of K5mOVA skin grafts by promoting generation of OVA-specific CD8 effector T cells in the skin-draining lymph nodes. This is associated with a decrease in the proportion of both Th17 cells and IL-17-producing NKT cells within the lymph node, thereby inducing a Th1-biased response by increasing the ratio of IFN-γ to IL-17 production. Administration of a strong agonist ligand (α-galactosylceramide) for NKT cells induced higher levels of local IFN-γ production, enhancing the rate of K5mOVA graft rejection. Thus, NKT cells can promote adaptive immunity to cell-associated Ag expressed in skin by local regulation of IFN-γ production in secondary lymphoid tissue during cross-priming of effector CD8 T cells. Skin integrity is controlled by a complex immunosurveillance network, vital for host survival. Maintaining a balance of active defense mechanisms to clear pathogens and prevent tumor development, and tolerogenic pathways to prevent chronic inflammation and autoimmunity, is critical to achieve immune homeostasis. Th17 cytokines have recently been associated with inflammatory processes in skin (1-3), once attributed solely to Th1 responses. Th1 and Th17 T cells are often colocalized in inflammatory skin environments; however, uncertainty exists in the relative contributions of IFN-γ and IL-17 and whether these cytokines work in synergism or are antagonistic (4-10). NKT cells regulate adaptive immunity to infections, cancer, and autoimmune reactions through production of Th1 (particularly IFN-γ) or Th2 (IL-4, IL-10, IL-13) cytokines, and have been implicated in skin diseases such as atopic dermatitis, psoriasis, and UV-induced skin cancer (reviewed in Ref. 11). Recent reports have provided convincing evidence that NKT cells are also capable of producing Th17 cytokines such as IL-21 (12), IL-22 (13), and IL-17 (14-19). IL-17 production by NKT cells was first characterized in a model of airway neutrophilia, revealing an NK1.1 − IL-17 + NKT subset in lungs (19). Further reports have