Functional interrogation of lymphocyte subsets in alopecia areata using single-cell RNA sequencing.
Functional interrogation of lymphocyte subsets in alopecia areata using single-cell RNA sequencing.
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DOI：
10.1073/pnas.2305764120
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发表时间：
2023-07-18
影响因子：
11.1
通讯作者：
Christiano, Angela M.
中科院分区：
文献类型：
--
作者：
Lee, Eunice Y.;Dai, Zhenpeng;Jaiswal, Abhinav;Wang, Eddy Hsi Chun;Anandasabapathy, Niroshana;Christiano, Angela M.
斑秃（AA）是一种常见的自身免疫性疾病，但由于对疾病机制的不完全理解，开发新的治疗方法的进展受到阻碍。使用scRNAseq单细胞RNA测序（scRNAseq），我们解剖了鼠和人AA皮肤的免疫景观，并耗尽了鼠AA中的特定细胞类型以询问它们的功能。我们证明CD 8 + T细胞是主要的疾病驱动细胞类型，其异质性由“效应梯度”定义，该梯度决定了其分化轨迹。我们的研究结果还揭示了Izumo 1 r/FR 4作为Treg（调节性T细胞）的标志物，其选择性消耗加速AA发作，证明了AA中完整的免疫抑制性Treg功能。小鼠和人类AA的共同机制突出了我们工作的翻译影响。斑秃（AA）是最常见的自身免疫性疾病之一，但由于对疾病的免疫学基础的不完全理解，创新治疗策略的开发一直滞后。在这里，我们进行了单细胞RNA测序（scRNAseq）的皮肤浸润免疫细胞从移植诱导的C3 H/HeJ小鼠模型的AA，再加上抗体为基础的耗竭，以询问特定的细胞类型在AA的功能作用在体内。由于AA主要是T细胞介导的，我们专注于解剖AA中的淋巴细胞功能。我们的scRNAseq和功能研究都确立了CD 8 + T细胞是AA中主要的疾病驱动细胞类型。只有CD 8 + T细胞的耗竭，而不是CD 4 + T细胞、NK、B或γδ T细胞的耗竭，才足以预防和逆转AA。调节性T细胞（Treg）的选择性耗竭显示Treg在C3 H/HeJ小鼠中对AA具有保护作用，表明Treg介导的免疫抑制的失败不是AA中的主要疾病机制。对CD 8 + T细胞的集中分析揭示了五个亚群，其异质性由相互关联的转录状态的“效应梯度”定义，其最终导致效应子功能和组织驻留增加。人AA皮肤的scRNAseq显示，人AA中的CD 8 + T细胞遵循类似的轨迹，强调了在鼠和人AA中驱动疾病的共同机制。我们的研究代表了AA中淋巴细胞异质性的全面，系统的询问，并揭示了AA相关CD 8 + T细胞的新框架，对未来治疗方法的设计具有影响。
Alopecia areata (AA) is a common autoimmune disorder, but progress in developing novel therapeutics has been hampered by an incomplete understanding of disease mechanisms. Using scRNAseq single-cell RNA sequencing (scRNAseq), we dissected the immune landscape of murine and human AA skin and depleted specific cell types in murine AA to interrogate their function. We demonstrated that CD8+ T cells are the predominant disease-driving cell type, whose heterogeneity is defined by an “effectorness gradient” that informs their trajectory of differentiation. Our results also uncovered Izumo1r/FR4 as a marker for Treg (regulatory T cells), whose selective depletion accelerated AA onset, demonstrating intact immunosuppressive Treg function in AA. Common mechanisms underlying murine and human AA highlight the translational impact of our work. Alopecia areata (AA) is among the most prevalent autoimmune diseases, but the development of innovative therapeutic strategies has lagged due to an incomplete understanding of the immunological underpinnings of disease. Here, we performed single-cell RNA sequencing (scRNAseq) of skin-infiltrating immune cells from the graft-induced C3H/HeJ mouse model of AA, coupled with antibody-based depletion to interrogate the functional role of specific cell types in AA in vivo. Since AA is predominantly T cell-mediated, we focused on dissecting lymphocyte function in AA. Both our scRNAseq and functional studies established CD8+ T cells as the primary disease-driving cell type in AA. Only the depletion of CD8+ T cells, but not CD4+ T cells, NK, B, or γδ T cells, was sufficient to prevent and reverse AA. Selective depletion of regulatory T cells (Treg) showed that Treg are protective against AA in C3H/HeJ mice, suggesting that failure of Treg-mediated immunosuppression is not a major disease mechanism in AA. Focused analyses of CD8+ T cells revealed five subsets, whose heterogeneity is defined by an “effectorness gradient” of interrelated transcriptional states that culminate in increased effector function and tissue residency. scRNAseq of human AA skin showed that CD8+ T cells in human AA follow a similar trajectory, underscoring that shared mechanisms drive disease in both murine and human AA. Our study represents a comprehensive, systematic interrogation of lymphocyte heterogeneity in AA and uncovers a novel framework for AA-associated CD8+ T cells with implications for the design of future therapeutics.
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影响因子：
13.6
作者：
Dai, Zhenpeng;Wang, Eddy Hsi Chun;Christiano, Angela M.
通讯作者：
Christiano, Angela M.
影响因子：
3.3
作者：
Chen, Meiyue;Chen, Guangjie;Hong, Jian
通讯作者：
Hong, Jian
影响因子：
32.4
作者：
Cao, Xuefang;Cai, Sheng F.;Ley, Timothy J.
通讯作者：
Ley, Timothy J.
影响因子：
12.4
作者：
Czarnowicki, T.;He, H. Y.;Guttman-Yassky, E.
通讯作者：
Guttman-Yassky, E.
影响因子：
1.5
作者：
Chruscinski A;Sadozai H;Rojas-Luengas V;Bartczak A;Khattar R;Selzner N;Levy GA
通讯作者：
Levy GA