PD-L1 on mast cells suppresses effector CD8+ T-cell activation in the skin in murine contact hypersensitivity.

Abstract Background The programmed cell death-1 (PD-1)/PD-ligand 1 (PD-L1) pathway is known to inhibit the activation of effector CD8+ T cells. However, it remains unclear how this regulatory pathway is involved in the pathophysiology of CD8+ T cell-mediated inflammatory skin diseases. Objective To elucidate the mechanisms by which the PD-1/PD-L1 pathway exerts its regulatory roles in CD8+ T cell-mediated cutaneous immune responses. Methods PD-L1 deficient (Pdl1-/-) mice were used for the murine contact hypersensitivity (CHS) model. Inflammatory responses such as interferon-γ (IFN-γ) production from CD8+ T cells in the skin was evaluated by flow cytometry. Results Pdl1-/- mice exhibited exacerbated ear swelling and increased number of IFN-γ+ CD8+ T cells in the skin compared to wild-type (WT) mice. Adoptive T cell transfer experiments revealed the involvement of the PD-1/PD-L1 pathway in the elicitation phase of CHS. Bone marrow chimera experiments showed that PD-L1 on radio-resistant cells was responsible for this regulatory pathway. Flow cytometric analysis revealed that among the radio-resistant cells in the skin, PD-L1 was most highly expressed on mast cells (MCs) before and after elicitation. Administration of anti-PD-L1 blocking antibody during the elicitation phase significantly enhanced ear swelling responses and increased the number of IFN-γ+ CD8+ T cells in the skin of WT mice, while no significant effects were observed in MC-deficient mice (WBB6F1/J-KitW/KitW-v/J and C57BL/6-KitW-sh/W-sh). High expression level of PD-L1 on human skin MCs was confirmed by database analysis and immunohistochemical analysis. Conclusion PD-L1 on MCs negatively regulates CD8+ T-cell activation in the skin.