Laboratory of Molecular Medicine, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan.
Division of Vaccinology for Clinical Development, Institute for Vaccine Research and Development (IVReD), Hokkaido University, Sapporo, Japan.
Front Immunol. 2024 Jan 29;15:1340467. doi: 10.3389/fimmu.2024.1340467. eCollection 2024.
Interleukin (IL)-17-producing γδT (γδT17) cells mediate inflammatory responses in barrier tissues. Dysregulated γδT17 cell activation can lead to the overproduction of IL-17 and IL-22 and the development of inflammatory diseases, including psoriasis. IL-23 and IL-1β are known to synergistically activate γδT17 cells, but the regulatory mechanisms of γδT17 cells have not been fully elucidated. This study aimed to reveal the contribution of the inflammatory cytokine tumor necrosis factor-like ligand 1A (TL1A) to γδT17 cell activation and psoriasis development.
Anti-TL1A antibody was injected into an imiquimod (IMQ)-induced murine psoriasis model. TL1A receptor expression was analyzed in splenic and dermal γδT cells. γδT cells were tested for cytokine production and under stimulation with IL-23, IL-1β, and TL1A. TL1A was applied to a psoriasis model induced by intradermal IL-23 injection. Mice deficient in γδT cells were intradermally injected with IL-23 plus TL1A to verify the contribution of TL1A-dependent γδT-cell activation to psoriasis development.
Neutralization of TL1A attenuated γδT17 cell activation in IMQ-treated skin. TL1A induced cytokine production by splenic γδT17 cells in synergy with IL-23. Dermal γδT17 cells constitutively expressed a TL1A receptor at high levels and vigorously produced IL-22 upon intradermal IL-23 and TL1A injection but not IL-23 alone. TL1A exacerbated the dermal symptoms induced by IL-23 injection in wild-type but not in γδT cell-deficient mice.
These findings suggest a novel regulatory mechanism of γδT cells through TL1A and its involvement in psoriasis pathogenesis as a possible therapeutic target.
白细胞介素 (IL)-17 产生的 γδT（γδT17）细胞在屏障组织中介导炎症反应。γδT17 细胞的异常激活可导致 IL-17 和 IL-22 的过度产生，并导致炎症性疾病的发展，包括银屑病。已知白细胞介素 23 (IL-23) 和白细胞介素 1β（IL-1β）协同激活 γδT17 细胞，但 γδT17 细胞的调节机制尚未完全阐明。本研究旨在揭示炎症细胞因子肿瘤坏死因子样配体 1A（TL1A）对 γδT17 细胞激活和银屑病发展的贡献。
在咪喹莫特 (IMQ) 诱导的小鼠银屑病模型中注射抗 TL1A 抗体。分析脾和皮肤 γδT 细胞中 TL1A 受体的表达。在 IL-23、IL-1β 和 TL1A 刺激下检测 γδT 细胞的细胞因子产生情况。在皮内注射 IL-23 诱导的银屑病模型中应用 TL1A。在皮内注射 IL-23 加 TL1A 验证 TL1A 依赖性 γδT 细胞激活对银屑病发展的贡献。
TL1A 中和减弱了 IMQ 处理皮肤中的 γδT17 细胞激活。TL1A 与 IL-23 协同诱导脾 γδT17 细胞产生细胞因子。皮肤 γδT17 细胞高表达 TL1A 受体，在皮内注射 IL-23 和 TL1A 时强烈产生 IL-22，但单独注射 IL-23 时则不然。TL1A 加剧了野生型小鼠中由 IL-23 注射引起的皮肤症状，但在 γδT 细胞缺陷型小鼠中则没有。
这些发现提示了 γδT 细胞通过 TL1A 的一种新的调节机制及其作为潜在治疗靶点参与银屑病发病机制。
