Tomoko Hirano1, Tetsuya Honda2, Shuto Kanameishi1, Yuki Honda1, Gyohei Egawa1, Akihiko Kitoh1, Saeko Nakajima1, Atsushi Otsuka1, Takashi Nomura1, Teruki Dainichi1, Tomonori Yaguchi3, Takashi Inozume4, Tatsuki R Kataoka5, Koji Tamada6, Kenji Kabashima7. 1. Department of Dermatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. 2. Department of Dermatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan. Electronic address: hontetsu@kuhp.kyoto-u.ac.jp. 3. Department of Immunology and Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan. 4. Department of Dermatology, Graduate School of Medicine, Chiba University, Chiba, Japan. 5. Department of Pathology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. 6. Department of Immunology, Graduate School of Medicine, Yamaguchi University, Yamaguchi, Japan. 7. Department of Dermatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Singapore Immunology Network (SIgN) and Skin Research Institute of Singapore, Agency for Science, Technology and Research, Biopolis, Singapore. Electronic address: kaba@kuhp.kyoto-u.ac.jp.
Abstract
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.
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.
Authors: Laura M Sipe; Mehdi Chaib; Emily B Korba; Heejoon Jo; Mary Camille Lovely; Brittany R Counts; Ubaid Tanveer; Jeremiah R Holt; Jared C Clements; Neena A John; Deidre Daria; Tony N Marion; Margaret S Bohm; Radhika Sekhri; Ajeeth K Pingili; Bin Teng; James A Carson; D Neil Hayes; Matthew J Davis; Katherine L Cook; Joseph F Pierre; Liza Makowski Journal: Elife Date: 2022-07-01 Impact factor: 8.713