Mucosal-associated invariant T cell-rich congenic mouse strain allows functional evaluation
Mucosal-associated invariant T cell-rich congenic mouse strain allows functional evaluation
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DOI：
10.1172/jci82424
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发表时间：
2015-11-01
影响因子：
15.9
通讯作者：
Lantz, Olivier
中科院分区：
文献类型：
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作者：
Cui, Yue;Franciszkiewicz, Katarzyna;Lantz, Olivier
粘膜相关的不变T细胞（MAIT）具有有效的抗微生物活性，在人体中大量存在（血液中占5%-10%）。尽管不变的TCR-α链和限制性分子MR 1具有很强的进化保守性，但该群体在实验室小鼠品系中很少见（在淋巴器官中约为0.1%），并且缺乏适当的小鼠模型阻碍了MAIT生物学的研究。在此，我们表明，MAIT是20倍更频繁的清洁野生衍生的近交系CAST/EiJ小鼠比C57 BL/6 J小鼠。MAIT频率增加与一种CAST遗传性状有关，该性状定位于TCR-α基因座，并导致远端V α片段（包括V α 19）的使用率更高。我们产生了MAIT（hl）同源菌株，然后将其与转基因Rorcgt-GFP报告菌株杂交。使用该工具，我们将多克隆小鼠MAIT表征为具有组织归巢特性的记忆（CD 44（+））CD 4（-）CD 8（lo/neg）T细胞（CCR 6 * CCR 7（-））。与人MAIT相似，小鼠MAIT表达细胞因子受体IL-7 R、IL-18 R α和IL-12 R β以及转录因子早幼粒细胞白血病锌指（PLZF）和RAR相关孤儿受体γ（RO R γ t）。小鼠MAIT在TCR刺激后产生Th 1/2/17细胞因子，并以MR 1依赖性方式识别细菌化合物。在实验性尿路感染期间，MAIT迁移到膀胱并降低细菌负荷。我们的研究表明，MAIT（hi）同源株允许在健康和疾病的自然发生的小鼠MAIT的表型和功能表征。
Mucosal-associated invariant T cells (MAITs) have potent antimicrobial activity and are abundant in humans (5%-10% in blood). Despite strong evolutionary conservation of the invariant TCR-alpha chain and restricting molecule MR1, this population is rare in laboratory mouse strains (approximate to 0.1% in lymphoid organs), and lack of an appropriate mouse model has hampered the study of MAIT biology. Herein, we show that MAITs are 20 times more frequent in clean wild-derived inbred CAST/EiJ mice than in C57BL/6J mice. Increased MAIT frequency was linked to one CAST genetic trait that mapped to the TCR-alpha locus and led to higher usage of the distal V alpha segments, including V alpha 19. We generated a MAIT(hl) congenic strain that was then crossed to a transgenic Rorcgt-GFP reporter strain. Using this tool, we characterized polyclonal mouse MAITs as memory (CD44(+)) CD4(-)CD8(lo/neg) T cells with tissue-homing properties (CCR6*CCR7(-)). Similar to human MAITs, mouse MAITs expressed the cytokine receptors IL-7R, IL-18R alpha, and IL-12R beta and the transcription factors promyelocytic leukemia zinc finger (PLZF) and RAR-related orphan receptory gamma (R0R gamma t). Mouse MAITs produced Th1/2/17 cytokines upon TCR stimulation and recognized a bacterial compound in an MR1-dependent manner. During experimental urinary tract infection, MAITs migrated to the bladder and decreased bacterial load. Our study demonstrates that the MAIT(hi) congenic strain allows phenotypic and functional characterization of naturally occurring mouse MAITs in health and disease.