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

人類修復(fù)相關(guān)雪旺細(xì)胞在體具有抗原呈遞細(xì)胞的功能

摘要雪旺細(xì)胞（SCs）的可塑性潛能因其在神經(jīng)損傷后和周圍神經(jīng)系統(tǒng)疾病中發(fā)揮作用而備受關(guān)注。有關(guān)免疫細(xì)胞和雪旺細(xì)胞之間相互作用的研究表明雪旺細(xì)胞參與炎癥過程。然而，人類雪旺細(xì)胞的免疫能力主要是從神經(jīng)病變中推斷出來的，但神經(jīng)損傷后雪旺細(xì)胞是否直接調(diào)節(jié)適應(yīng)性免疫反應(yīng)尚不清楚。本研究對人類修復(fù)相關(guān)雪旺細(xì)胞（hrSCs）的免疫調(diào)節(jié)能力進行綜合分析，hrSCs概括了雪旺細(xì)胞對體外神經(jīng)損傷的反應(yīng)。我們使用有效的人類周圍神經(jīng)原代hrSCs 培養(yǎng)模型，分析了轉(zhuǎn)錄組、分泌組、以及細(xì)胞表面與先天免疫和適應(yīng)性免疫相關(guān)的通路和標(biāo)志物相關(guān)的蛋白；進行了吞噬作用測定，并監(jiān)測了同種異體共培養(yǎng)細(xì)胞中的T 細(xì)胞亞群激活。本研究結(jié)果表明hrSC 具有吞噬作用，這與MHCⅡ的高表達一致。此外，hrSC 表達協(xié)同調(diào)節(jié)蛋白，如CD40、CD80、B7H3、CD58、CD86 和HVEM，釋放過多的趨化因子、基質(zhì)重塑蛋白、促炎及抗炎細(xì)胞因子，并在IFNγ 進行促炎刺激后上調(diào)T 細(xì)胞對PD-L1 分子的抑制。與單核細(xì)胞相反，單獨的hrSC 不足以觸發(fā)同種異體CD4+和CD8+T 細(xì)胞，但會限制外源激活的T 細(xì)胞的數(shù)量和激活狀態(tài)。本研究表明，hrSCs 具有體外專職抗原呈遞細(xì)胞的典型特征和功能，并表明這些細(xì)胞在神經(jīng)再生過程中作為T 細(xì)胞免疫負(fù)調(diào)節(jié)劑的新作用。

關(guān)鍵詞PD-L1；雪旺細(xì)胞；抗原呈遞細(xì)胞；免疫能力；免疫調(diào)節(jié)；炎癥；神經(jīng)損傷；神經(jīng)病變

中圖分類號R741；R741.02文獻標(biāo)識碼ADOI10.16780/j.cnki.sjssgncj.2022.11.017