Human repair-related Schwann cells adopt functions of antigen-presenting cells in vitro*

Jakob Berner,Tamara Weiss,Helena Sorger,Fikret Rifatbegovic,Max Kauer,Reinhard Windhager,Alexander Dohnal,Peter F Ambros,Inge M Ambros,Kaan Boztug,5,6,Peter Steinberger,Sabine Taschner-Mandl

1.St.Anna Children's Cancer Research Institute(CCRI),Vienna,Austria.2.St.Anna Children's Hospital,Vienna,Austria.3.Department of Plastic,Reconstructive and Aesthetic Surgery,Medical University of Vienna.4.Department of Orthopedics and Trauma Surgery,Medical University of Vienna,Vienna,Austria.5.Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases(LBI-RUD),Vienna,Austria.6.Center for Molecular Medicine(CeMM),Vienna,Austria.7.Institute of Immunology,Medical University of Vienna,Vienna,Austria.

Abstract The plastic potential of Schwann cells(SCs)is increasingly recognized to play a role after nerve injury and in diseases of the peripheral nervous system.Reports on the interaction between immune cells and SCs indicate their involvement in inflammatory processes.However,the immunocompetence of human SCs has been primarily deduced from neuropathies,but whether after nerve injury SCs directly regulate an adaptive immune response is unknown.Here,we performed comprehensive analysis of immunomodulatory capacities of human repair-related SCs (hrSCs),which recapitulate SC response to nerve injury in vitro.We used our well-established culture model of primary hrSCs from human peripheral nerves and analyzed the transcriptome,secretome,and cell surface proteins for pathways and markers relevant in innate and adaptive immunity,performed phagocytosis assays,and monitored T-cell subset activation in allogeneic co-cultures.Our findings show that hrSCs are phagocytic,which is in line with high MHCII expression.Furthermore,hrSCs express co-regulatory proteins,such as CD40,CD80,B7H3,CD58,CD86,and HVEM,release a plethora of chemoattractants,matrix remodeling proteins and pro- as well as anti-inflammatory cytokines,and upregulate the T-cell inhibiting PD-L1 molecule upon pro-inflammatory stimulation with IFNγ.In contrast to monocytes,hrSC alone are not sufficient to trigger allogenic CD4+and CD8+T-cells,but limit number and activation status of exogenously activated T-cells.This study demonstrates that hrSCs possess features and functions typical for professional antigen-presenting cells in vitro,and suggest a new role of these cells as negative regulators of T-cell immunity during nerve regeneration.

Keywords PD-L1; Schwann cell; antigen-presenting cell; immunocompetence; immunoregulatory; inflammation;nerve injury;neuropathies

人类修复相关雪旺细胞在体具有抗原呈递细胞的功能

摘要雪旺细胞（SCs）的可塑性潜能因其在神经损伤后和周围神经系统疾病中发挥作用而备受关注。有关免疫细胞和雪旺细胞之间相互作用的研究表明雪旺细胞参与炎症过程。然而，人类雪旺细胞的免疫能力主要是从神经病变中推断出来的，但神经损伤后雪旺细胞是否直接调节适应性免疫反应尚不清楚。本研究对人类修复相关雪旺细胞（hrSCs）的免疫调节能力进行综合分析，hrSCs概括了雪旺细胞对体外神经损伤的反应。我们使用有效的人类周围神经原代hrSCs 培养模型，分析了转录组、分泌组、以及细胞表面与先天免疫和适应性免疫相关的通路和标志物相关的蛋白；进行了吞噬作用测定，并监测了同种异体共培养细胞中的T 细胞亚群激活。本研究结果表明hrSC 具有吞噬作用，这与MHCⅡ的高表达一致。此外，hrSC 表达协同调节蛋白，如CD40、CD80、B7H3、CD58、CD86 和HVEM，释放过多的趋化因子、基质重塑蛋白、促炎及抗炎细胞因子，并在IFNγ 进行促炎刺激后上调T 细胞对PD-L1 分子的抑制。与单核细胞相反，单独的hrSC 不足以触发同种异体CD4+和CD8+T 细胞，但会限制外源激活的T 细胞的数量和激活状态。本研究表明，hrSCs 具有体外专职抗原呈递细胞的典型特征和功能，并表明这些细胞在神经再生过程中作为T 细胞免疫负调节剂的新作用。

关键词PD-L1；雪旺细胞；抗原呈递细胞；免疫能力；免疫调节；炎症；神经损伤；神经病变

中图分类号R741；R741.02文献标识码ADOI10.16780/j.cnki.sjssgncj.2022.11.017