Insights into Keratinocyte and Immunologic Landscape in Cutaneous Graft-Versus-Host Disease through Single-Cell Transcriptomics

Amy J. Petty , Adela Rambi Cardones , Yingai Jane Jin , Vaibhav Jain , Emily Hocke , Harsh B. Pathak , Amrita Mitra , Simon G. Gregory , M. Angelica Selim , Jennifer Y. Zhang
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Abstract

Cutaneous manifestations are the most common presenting sign of chronic graft-versus-host disease (GVHD), and the extent of cutaneous involvement is also highly correlated with prognosis. Very little is understood about the underlying pathogenesis underpinning injury at this location, especially the contribution of keratinocytes and other structural skin cells. We performed single-cell RNA sequencing to compare the transcriptome of epidermal and dermal chronic GVHD samples with that of healthy control samples. Our findings reveal unique nonimmunologic and immunologic changes in epidermal keratinocytes and dermal immune cells. Specifically, we observed upregulation of alarmins and inflammatory cytokines and downregulation of anti-reduction–oxidation and activator protein-1 pathway genes in the keratinocyte compartments. In dermal immune cell subsets, we showed increased CD8+ T, CD4+ T, CD4+Foxp3+ regulatory T, and NK cells in chronic GVHD, accompanied by increased signals of leukocyte functions, inflammatory responses, cytolysis, and macrophage M1 polarization. Finally, we also delineated the donor versus recipient cellular origin of nonimmune and immune cell populations in sex-mismatched chronic GVHD. Taken together, these data reveal complex keratinocyte and immune responses in cutaneous chronic GVHD, supporting future studies of skin cell contributions to pathogenesis and potential local treatment strategies.
通过单细胞转录组学研究皮肤移植物抗宿主病的角化细胞和免疫景观
皮肤表现是慢性移植物抗宿主病(GVHD)最常见的表现,皮肤受累程度也与预后高度相关。目前对该部位损伤的潜在发病机制知之甚少,尤其是角质形成细胞和其他结构性皮肤细胞的作用。我们进行单细胞RNA测序,比较表皮和真皮慢性GVHD样本与健康对照样本的转录组。我们的发现揭示了表皮角质形成细胞和真皮免疫细胞独特的非免疫和免疫变化。具体来说,我们观察到角化细胞室中报警因子和炎症细胞因子的上调以及抗还原氧化和激活蛋白1通路基因的下调。在皮肤免疫细胞亚群中,我们发现慢性GVHD患者的CD8+ T、CD4+ T、CD4+Foxp3+调节性T和NK细胞增加,同时白细胞功能、炎症反应、细胞溶解和巨噬细胞M1极化信号增加。最后,我们还描述了性别不匹配的慢性GVHD中非免疫和免疫细胞群的供体与受体细胞起源。综上所述,这些数据揭示了皮肤慢性GVHD中复杂的角化细胞和免疫反应,支持了皮肤细胞对发病机制和潜在局部治疗策略的未来研究。
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