The Journal of allergy and clinical immunology · 2021
PD-L1 on mast cells suppresses effector CD8+ T-cell activation in the skin in murine contact hypersensitivity.
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Hirano Tomoko, Honda Tetsuya, Kanameishi Shuto, Honda Yuki, Egawa Gyohei, Kitoh Akihiko, Nakajima Saeko, Otsuka Atsushi, Nomura Takashi, Dainichi Teruki, Yaguchi Tomonori, Inozume Takashi, Kataoka Tatsuki R, Tamada Koji, Kabashima Kenji
Аннотация
BACKGROUND: The programmed cell death-1 (PD-1)/programmed death ligand 1 (PD-L1) pathway is known to inhibit the activation of effector CD8+ T cells. However, just how this regulatory pathway is involved in the pathophysiology of CD8+ T-cell-mediated inflammatory skin diseases remains unclear.
OBJECTIVE: Our aim was 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 model. Inflammatory responses such as IFN-γ production from CD8+ T cells in the skin was evaluated by flow cytometry.
RESULTS: Compared with wild-type mice, Pdl1-/- mice exhibited exacerbated ear swelling and increased numbers of IFN-γ+ CD8+ T cells in the skin. Adoptive T-cell transfer experiments revealed the involvement of the PD-1/PD-L1 pathway in the elicitation phase of contact hypersensitivity. Bone marrow chimera experiments showed that PD-L1 on radioresistant cells was responsible for this regulatory pathway. Flow cytometric analysis revealed that among the radioresistant 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 wild-type mice, whereas no significant effects were observed in MC-deficient (WBB6F1/J-KitW/KitW-v/J and C57BL/6-KitW-sh/W-sh) mice. The high level of expression 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.
OBJECTIVE: Our aim was 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 model. Inflammatory responses such as IFN-γ production from CD8+ T cells in the skin was evaluated by flow cytometry.
RESULTS: Compared with wild-type mice, Pdl1-/- mice exhibited exacerbated ear swelling and increased numbers of IFN-γ+ CD8+ T cells in the skin. Adoptive T-cell transfer experiments revealed the involvement of the PD-1/PD-L1 pathway in the elicitation phase of contact hypersensitivity. Bone marrow chimera experiments showed that PD-L1 on radioresistant cells was responsible for this regulatory pathway. Flow cytometric analysis revealed that among the radioresistant 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 wild-type mice, whereas no significant effects were observed in MC-deficient (WBB6F1/J-KitW/KitW-v/J and C57BL/6-KitW-sh/W-sh) mice. The high level of expression 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.