Functional Heterogeneity and Antimycobacterial Effects of Mouse Mucosal-Associated Invariant T Cells Specific for Riboflavin Metabolites.
Functional Heterogeneity and Antimycobacterial Effects of Mouse Mucosal-Associated Invariant T Cells Specific for Riboflavin Metabolites.
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DOI：
10.4049/jimmunol.1402545
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发表时间：
2015-07-15
期刊：
影响因子：
--
通讯作者：
Hoft DF
中科院分区：
文献类型：
--
作者：
Sakala IG;Kjer-Nielsen L;Eickhoff CS;Wang X;Blazevic A;Liu L;Fairlie DP;Rossjohn J;McCluskey J;Fremont DH;Hansen TH;Hoft DF
粘膜相关不变T细胞(MAIT)具有半不变的TCRVα链，它们的最佳发育依赖于共生菌群和非多态的MHC I类分子MR1的表达。MAIT细胞被不同菌株的细菌和酵母菌以MR1限制性的方式激活，这表明存在广泛共享的Ag。最近，人和小鼠的MR1被发现与细菌核黄素代谢产物(核黄素核黄素代谢物，RL-Ag)结合，能够激活MAIT细胞。在这里，我们使用MR1/RL四聚体来研究MR1依赖性、亚群异质性和保护效应功能对结核病免疫的重要作用。虽然在mr1+/+和mr1−/−TCRVα19i转基因(TG)小鼠中都检测到四聚体+细胞，但mR1的表达导致共表达TCRV CD6/8、NK1.1、CD44和CD69的四聚体+细胞显著增加，在体外对IL-12+IL-18和RL-Ag表现出更强的反应，表明mR1对经典的小鼠β记忆/效应亚群的最佳发育是必需的。此外，在MR1+/+Vα19ITG小鼠中，表达CD_4、CD_8的四聚体+MAIT细胞或不表达CD_4、CD_8的四聚体+MAIT细胞对RL抗原的反应具有不同的细胞因子谱。因此，小鼠MAIT细胞的异质性比之前认为的要多得多。最值得注意的是，在分枝杆菌肺部感染后，表达CXCR3和α4β1的四聚体+V CXCR19i TG MAIT细胞的异质性亚群被招募到肺内并提供早期保护。此外，Vα19iCα−/−MR+/+小鼠的免疫保护作用明显好于Vα19iCα−/−mr1−/−、野生型和mr1−/−非转基因小鼠。总体而言，我们展示了MAIT细胞反应的相当大的功能多样性，并且MR1限制的MAIT细胞对于结核病保护性免疫是重要的。
Mucosal associated invariant T (MAIT) cells have a semi-invariant TCR Vα chain, and their optimal development is dependent upon commensal flora and expression of the non-polymorphic MHC class I-like molecule MR1. MAIT cells are activated in an MR1-restricted manner by diverse strains of bacteria and yeast suggesting a widely shared Ag. Recently, human and mouse MR1 were found to bind bacterial riboflavin metabolites (ribityllumazines, RL Ag) capable of activating MAIT cells. Here we use MR1/RL tetramers to study MR1-dependency, subset heterogeneity and protective effector functions important for tuberculosis (TB) immunity. Although tetramer+ cells were detected in both MR1+/+ and MR1−/− TCR Vα19i transgenic (Tg) mice, MR1 expression resulted in significantly increased tetramer+ cells co-expressing TCR Vβ6/8, NK1.1, CD44 and CD69, that displayed more robust in vitro responses to IL-12+IL-18 and RL Ag, indicating that MR1 is necessary for the optimal development of the classic murine MAIT cell memory/effector subset. In addition, tetramer+ MAIT cells expressing CD4, CD8 or neither developing in MR1+/+ Vα19i Tg mice had disparate cytokine profiles in response to RL Ag. Therefore, murine MAIT cells are considerably more heterogeneous than previously thought. Most notably, after mycobacterial pulmonary infection heterogeneous subsets of tetramer+ Vα19i Tg MAIT cells expressing CXCR3 and α4β1 were recruited into the lungs and afforded early protection. In addition, Vα19iCα−/−MR+/+ mice were significantly better protected than Vα19iCα−/−MR1−/−, wild type and MR1−/− non-transgenic mice. Overall, we demonstrate considerable functional diversity of MAIT cell responses, and also that MR1-restricted MAIT cells are important for TB protective immunity.
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影响因子：
4.4
作者：
Feng, CG;Britton, WJ;Bean, AGD
通讯作者：
Bean, AGD
影响因子：
15.3
作者：
Arase, N;Arase, H;Saito, T
通讯作者：
Saito, T
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
影响因子：
7.3
作者：
Bartel Y;Bauer B;Steinle A
通讯作者：
Steinle A
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