Suppression of MR1 by human cytomegalovirus inhibits MAIT cell activation.
Suppression of MR1 by human cytomegalovirus inhibits MAIT cell activation.
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DOI：
10.3389/fimmu.2023.1107497
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发表时间：
2023
影响因子：
7.3
通讯作者：
Slobedman, Barry
中科院分区：
文献类型：
--
作者：
Ashley, Caroline L.;McSharry, Brian P.;McWilliam, Hamish E. G.;Stanton, Richard J.;Fielding, Ceri A.;Mathias, Rommel A.;Fairlie, David P.;McCluskey, James;Villadangos, Jose A.;Rossjohn, Jamie;Abendroth, Allison;Slobedman, Barry
关键词：
抗原呈递分子MHC I类相关蛋白-1（MR 1）的最佳特征在于其将维生素B2生物合成的细菌衍生代谢物呈递给粘膜相关不变T细胞（MAIT细胞）的能力。通过在体外人巨细胞病毒（HCMV）感染的MR 1配体的存在下，我们研究的调制MR 1的表达。使用免疫共沉淀，质谱，表达重组腺病毒和HCMV缺失突变体，我们调查HCMV gpUS 9及其家族成员作为潜在的调节MR 1的表达。通过HCMV感染的MR 1调节的功能后果在共培养活化测定中探索，所述共培养活化测定具有经工程化以表达MAIT细胞TCR的Jurkat细胞或原代MAIT细胞。通过添加MR 1中和抗体和CRISPR/Cas-9介导的MR 1敲除来建立这些活化测定中的MR 1依赖性。在这里，我们证明HCMV感染有效抑制MR 1表面表达并降低MR 1总蛋白水平。病毒糖蛋白gpUS 9的单独表达可以降低细胞表面和总MR 1水平，对特定US 9 HCMV缺失突变体的分析表明病毒可以使用多种机制靶向MR 1。使用原代MAIT细胞的功能测定证明了HCMV感染抑制细菌驱动的、使用中和抗体和工程化的MR 1敲除细胞的MR 1依赖性活化的能力。本研究确定了HCMV编码的破坏MR 1：MAIT细胞轴的策略。这种免疫轴在病毒感染的情况下不太好地表征。HCMV编码数百种蛋白质，其中一些调节抗原呈递分子的表达。然而，该病毒调节MR 1：MAIT TCR轴的能力尚未详细研究。
The antigen presentation molecule MHC class I related protein-1 (MR1) is best characterized by its ability to present bacterially derived metabolites of vitamin B2 biosynthesis to mucosal-associated invariant T-cells (MAIT cells). Through in vitro human cytomegalovirus (HCMV) infection in the presence of MR1 ligand we investigate the modulation of MR1 expression. Using coimmunoprecipitation, mass spectrometry, expression by recombinant adenovirus and HCMV deletion mutants we investigate HCMV gpUS9 and its family members as potential regulators of MR1 expression. The functional consequences of MR1 modulation by HCMV infection are explored in coculture activation assays with either Jurkat cells engineered to express the MAIT cell TCR or primary MAIT cells. MR1 dependence in these activation assays is established by addition of MR1 neutralizing antibody and CRISPR/Cas-9 mediated MR1 knockout. Here we demonstrate that HCMV infection efficiently suppresses MR1 surface expression and reduces total MR1 protein levels. Expression of the viral glycoprotein gpUS9 in isolation could reduce both cell surface and total MR1 levels, with analysis of a specific US9 HCMV deletion mutant suggesting that the virus can target MR1 using multiple mechanisms. Functional assays with primary MAIT cells demonstrated the ability of HCMV infection to inhibit bacterially driven, MR1-dependent activation using both neutralizing antibodies and engineered MR1 knockout cells. This study identifies a strategy encoded by HCMV to disrupt the MR1:MAIT cell axis. This immune axis is less well characterized in the context of viral infection. HCMV encodes hundreds of proteins, some of which regulate the expression of antigen presentation molecules. However the ability of this virus to regulate the MR1:MAIT TCR axis has not been studied in detail.
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影响因子：
8
作者：
Gibbs A;Leeansyah E;Introini A;Paquin-Proulx D;Hasselrot K;Andersson E;Broliden K;Sandberg JK;Tjernlund A
通讯作者：
Tjernlund A
影响因子：
64.5
作者：
Brodin P;Jojic V;Gao T;Bhattacharya S;Angel CJ;Furman D;Shen-Orr S;Dekker CL;Swan GE;Butte AJ;Maecker HT;Davis MM
通讯作者：
Davis MM
影响因子：
4.3
作者：
Bhattacharyya, Abir;Hanafi, Laila-Aicha;Turtle, Cameron J.
通讯作者：
Turtle, Cameron J.
影响因子：
9.8
作者：
Gold MC;Cerri S;Smyk-Pearson S;Cansler ME;Vogt TM;Delepine J;Winata E;Swarbrick GM;Chua WJ;Yu YY;Lantz O;Cook MS;Null MD;Jacoby DB;Harriff MJ;Lewinsohn DA;Hansen TH;Lewinsohn DM
通讯作者：
Lewinsohn DM
DOI：
10.1084/jem.20140484
发表时间：
2014-07-28
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Eckle SB;Birkinshaw RW;Kostenko L;Corbett AJ;McWilliam HE;Reantragoon R;Chen Z;Gherardin NA;Beddoe T;Liu L;Patel O;Meehan B;Fairlie DP;Villadangos JA;Godfrey DI;Kjer-Nielsen L;McCluskey J;Rossjohn J
通讯作者：
Rossjohn J