Maeda Kohei, Tanioka Toshihiro, Takahashi Rei, Watanabe Hideaki, Sueki Hirohiko, Takimoto Masafumi, Hashimoto Shin-Ichi, Ikeo Kazuho, Miwa Yusuke, Kasama Tsuyoshi, Iwamoto Sanju
Division of Physiology and Pathology, Department of Pharmacology, Toxicology, and Therapeutics, Showa University School of Pharmacy, Tokyo, Japan.
Department of Dermatology, Showa University School of Medicine, Tokyo, Japan.
J Immunol. 2023 Jun 15;210(12):1867-1881. doi: 10.4049/jimmunol.2200530.
Recent studies have highlighted the pathogenic roles of IL-17-producing CD8+ T cells (T-cytotoxic 17 [Tc17]) in psoriasis. However, the underlying mechanisms of Tc17 induction remain unclear. In this study, we focused on the pathogenic subsets of Th17 and their mechanism of promotion of Tc17 responses. We determined that the pathogenic Th17-enriched fraction expressed melanoma cell adhesion molecule (MCAM) and CCR6, but not CD161, because this subset produced IL-17A abundantly and the presence of these cells in the peripheral blood of patients has been correlated with the severity of psoriasis. Intriguingly, the serial analysis of gene expression revealed that CCR6+MCAM+CD161-CD4+ T cells displayed the gene profile for adaptive immune responses, including CD83, which is an activator for CD8+ T cells. Coculture assay with or without intercellular contact between CD4+ and CD8+ T cells showed that CCR6+MCAM+CD161-CD4+ T cells induced the proliferation of CD8+ T cells in a CD83-dependent manner. However, the production of IL-17A by CD8+ T cells required exogenous IL-17A, suggesting that intercellular contact via CD83 and the production of IL-17A from activated CD4+ T cells elicit Tc17 responses. Intriguingly, the CD83 expression was enhanced in the presence of IL-15, and CD83+ cells stimulated with IL-1β, IL-23, IL-15, and IL-15Rα did not express FOXP3. Furthermore, CCR6+MCAM+CD161-CD4+ T cells expressing CD83 were increased in the peripheral blood of patients, and the CD83+ Th17-type cells accumulated in the lesional skin of psoriasis. In conclusion, pathogenic MCAM+CD161- Th17 cells may be involved in the Tc17 responses via IL-17A and CD83 in psoriasis.
近期研究突出了产生白细胞介素-17的CD8+T细胞（细胞毒性T细胞17 [Tc17]）在银屑病中的致病作用。然而，Tc17诱导的潜在机制仍不清楚。在本研究中，我们聚焦于Th17的致病亚群及其促进Tc17反应的机制。我们确定，富含致病性Th17的部分表达黑色素瘤细胞黏附分子（MCAM）和CCR6，但不表达CD161，因为该亚群大量产生白细胞介素-17A，且患者外周血中这些细胞的存在与银屑病的严重程度相关。有趣的是，基因表达序列分析显示，CCR6+MCAM+CD161-CD4+T细胞呈现适应性免疫反应的基因谱，包括作为CD8+T细胞激活剂的CD83。CD4+和CD8+T细胞之间有无细胞间接触的共培养试验表明，CCR6+MCAM+CD161-CD4+T细胞以CD83依赖的方式诱导CD8+T细胞增殖。然而，CD8+T细胞产生白细胞介素-17A需要外源性白细胞介素-17A，这表明通过CD83的细胞间接触以及活化的CD4+T细胞产生白细胞介素-17A引发了Tc17反应。有趣的是，在白细胞介素-15存在的情况下CD83表达增强，并且用白细胞介素-1β、白细胞介素-23、白细胞介素-15和白细胞介素-15Rα刺激的CD83+细胞不表达叉头框蛋白P3（FOXP3）。此外，表达CD83的CCR6+MCAM+CD161-CD4+T细胞在患者外周血中增多，并且CD83+Th17型细胞在银屑病皮损中积聚。总之，致病性MCAM+CD161-Th17细胞可能通过白细胞介素-17A和CD83参与银屑病中的Tc17反应。
