Group A Streptococcus induces CD1a-autoreactive T cells and promotes psoriatic inflammation
Group A Streptococcus induces CD1a-autoreactive T cells and promotes psoriatic inflammation
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DOI：
10.1126/sciimmunol.add9232
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发表时间：
2023-06-01
影响因子：
24.8
通讯作者：
Ogg，Graham S.
中科院分区：
文献类型：
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作者：
Chen，Yi-Ling;Ng，Jessica Soo Weei;Ogg，Graham S.
群链球菌（GAS）感染与多种临床后遗症相关，包括不同亚型的牛皮癣。这种链球菌后疾病早已为人所知，但在很大程度上无法解释。CD1a在朗格汉斯细胞中以组成性高水平表达，并向T细胞提供脂质抗原，但尚未研究其与GAS感染的潜在相关性。在这里，我们研究了gas反应性cd1a限制性T细胞是否参与牛皮癣的发病机制。健康个体具有高频率的循环和皮肤气体应答CD4+和CD8+T细胞，具有快速效应功能，包括产生白细胞介素-22 （IL-22）。人类皮肤和血液中产生il -22的T细胞的单细胞CITE-seq分析显示具有增殖潜力的17型特征，而产生IFN-γ的T细胞显示细胞毒性T淋巴细胞特征。此外，牛皮癣患者循环gas反应性T细胞的频率明显更高，这些T细胞富含活化、细胞溶解电位和组织关联的标志物。除了对GAS有反应外，扩增的GAS反应性T细胞克隆/系的亚群被发现具有自身反应性，其中包括对自身脂质抗原溶血磷脂酰胆碱的识别。CD8+T细胞克隆/系产生细胞溶解介质并裂解受感染的表达cd1a的细胞。此外，我们在人源化CD1a转基因小鼠模型中建立了GAS感染的皮肤模型，并发现局部和全身炎症增强和延长，并通过牛皮癣样表型解决。总之，这些发现将GAS感染与CD1a途径联系起来，并表明GAS感染促进CD1a自身反应性T细胞的增殖和激活，与链球菌感染后疾病相关，包括牛皮癣的发病机制和治疗。
Group AStreptococcus(GAS) infection is associated with multiple clinical sequelae, including different subtypes of psoriasis. Such post-streptococcal disorders have been long known but are largely unexplained. CD1a is expressed at constitutively high levels by Langerhans cells and presents lipid antigens to T cells, but the potential relevance to GAS infection has not been studied. Here, we investigated whether GAS-responsive CD1a-restricted T cells contribute to the pathogenesis of psoriasis. Healthy individuals had high frequencies of circulating and cutaneous GAS-responsive CD4+and CD8+T cells with rapid effector functions, including the production of interleukin-22 (IL-22). Human skin and blood single-cell CITE-seq analyses of IL-22–producing T cells showed a type 17 signature with proliferative potential, whereas IFN-γ–producing T cells displayed cytotoxic T lymphocyte characteristics. Furthermore, individuals with psoriasis had significantly higher frequencies of circulating GAS-reactive T cells, enriched for markers of activation, cytolytic potential, and tissue association. In addition to responding to GAS, subsets of expanded GAS-reactive T cell clones/lines were found to be autoreactive, which included the recognition of the self-lipid antigen lysophosphatidylcholine. CD8+T cell clones/lines produced cytolytic mediators and lysed infected CD1a-expressing cells. Furthermore, we established cutaneous models of GAS infection in a humanized CD1a transgenic mouse model and identified enhanced and prolonged local and systemic inflammation, with resolution through a psoriasis-like phenotype. Together, these findings link GAS infection to the CD1a pathway and show that GAS infection promotes the proliferation and activation of CD1a-autoreactive T cells, with relevance to post-streptococcal disease, including the pathogenesis and treatment of psoriasis.