CCR4+CD8+ T 细胞在小鼠银屑病和人类银屑病关节炎中克隆扩增为分化效应细胞,European Journal of Immunology

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CCR4+CD8+ T 细胞在小鼠银屑病和人类银屑病关节炎中克隆扩增为分化效应细胞
European Journal of Immunology ( IF 4.5 ) Pub Date : 2023-02-01 , DOI: 10.1002/eji.202149702
Guendalina Montico ₁ , Francesca Mingozzi ₂ , Fabio Casciano _{3,

4} , Giulia Protti _{2,

5} , Laura Gornati ₂ , Erika Marzola ₆ , Giuseppe Banfi ₁ , Remo Guerrini ₆ , Paola Secchiero ₃ , Stefano Volinia _{3,

7} , Francesca Granucci ₂ , Eva Reali ₂

Affiliation

银屑病是一种慢性炎症性皮肤病，具有自身免疫成分，在高达 30% 的病例中与关节炎症相关。为了研究自身反应性 T 细胞，我们在 K5-mOVA.tg C57BL/6 小鼠中开发了一种咪喹莫特诱导的银屑病样炎症模型，该小鼠在角质形成细胞膜上表达卵清蛋白 (OVA)，过继转移了 OT-I OVA 特异性 CD8 + ^T细胞. ^{我们评估了 OT-I CD8 +} T 细胞的扩增及其在皮肤、血液和脾脏中的定位。还分析了银屑病关节炎患者的 scRNA-seq 和 TCR 测序数据。在咪喹莫特处理的 K5-mOVA.tg 小鼠模型中，OT-I T 细胞在早期时间点在皮肤和血液中显着扩增。皮肤中的OT-I T细胞主要表现为CXCR3 ⁺效应记忆表型，而在外周血中存在 CCR4 ⁺ CXCR3 ⁺ OT-I 细胞的扩增。在稍后的时间点，在脾脏中发现了扩增的 OVA 特异性 T 细胞群。在银屑病关节炎患者中，scRNA-seq 和 TCR 测序数据显示 CCR4 ⁺ T _CM细胞在循环中克隆扩增，并在滑液中进一步扩增。重要的是，外周血中的CCR4 ⁺ T _{CM与 CD8}⁺之间存在克隆型重叠滑液中的 T 细胞效应器。这种机制可能在自身反应性 T 细胞的产生和扩散到有发展为银屑病关节炎风险的银屑病患者的滑膜附着组织中发挥作用。

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CCR4+CD8+ T cells clonally expand to differentiated effectors in murine psoriasis and in human psoriatic arthritis

Psoriasis is a chronic inflammatory skin disease with an autoimmune component and associated with joint inflammation in up to 30% of cases. To investigate autoreactive T cells, we developed an imiquimod-induced psoriasis-like inflammation model in K5-mOVA.tg C57BL/6 mice expressing ovalbumin (OVA) on the keratinocyte membrane, adoptively transferred with OT-I OVA-specific CD8⁺ T cells. We evaluated the expansion of OT-I CD8⁺ T cells and their localization in skin, blood, and spleen. scRNA-seq and TCR sequencing data from patients with psoriatic arthritis were also analyzed. In the imiquimod-treated K5-mOVA.tg mouse model, OT-I T cells were markedly expanded in the skin and blood at early time points. OT-I T cells in the skin showed mainly CXCR3⁺ effector memory phenotype, whereas in peripheral blood there was an expansion of CCR4⁺CXCR3⁺ OT-I cells. At a later time point, expanded OVA-specific T-cell population was found in the spleen. In patients with psoriatic arthritis, scRNA-seq and TCR sequencing data showed clonal expansion of CCR4⁺ T_CM cells in the circulation and further expansion in the synovial fluid. Importantly, there was a clonotype overlap between CCR4⁺ T_CM in the peripheral blood and CD8⁺ T-cell effectors in the synovial fluid. This mechanism could play a role in the generation and spreading of autoreactive T cells to the synovioentheseal tissues in psoriasis patients at risk of developing psoriatic arthritis.

更新日期：2023-02-01

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