Stepwise development of MAIT cells in mouse and human.
Stepwise development of MAIT cells in mouse and human.
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DOI：
10.1371/journal.pbio.1000054
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发表时间：
2009-03-10
期刊：
影响因子：
9.8
通讯作者：
Lantz O
中科院分区：
文献类型：
--
作者：
Martin E;Treiner E;Duban L;Guerri L;Laude H;Toly C;Premel V;Devys A;Moura IC;Tilloy F;Cherif S;Vera G;Latour S;Soudais C;Lantz O
粘膜相关的不变性T细胞（MAIT）表现出两个进化上保守的特征：不变性T细胞受体(TCR)α (iTCRα)链和非多态性Ib类主要组织相容性复合体（MHC）分子，MHC相关分子1 （MR1）的限制。胸腺上皮细胞上MR1的表达不是MAIT细胞发育所必需的，但它们在肠道中的积累需要MR1表达的B细胞和共生菌群。MAIT细胞的发育鲜为人知，因为这些细胞到目前为止还没有在胸腺中发现。本研究利用抗人v α7.2抗体和不同遗传背景的MAIT细胞特异性iTCRα和TCRβ转基因小鼠进行了人和小鼠的互补实验，结果表明，MAIT细胞的发育是一个循序渐进的过程，先是胸腺内选择，然后是外周扩增。小鼠MAIT细胞在胎儿胸腺器官培养和双iTCRα和TCRβ转基因RAG敲除小鼠中均以mr1依赖的方式被选择。在后一种小鼠中，MAIT细胞不会在外周扩增，除非通过过继转移加入B细胞，这表明B细胞不是最初胸腺选择步骤所需要的，而是外周积累所需要的。在人类中，与自然杀伤T细胞（NKT）相反，MAIT细胞在胸腺和脐带血中表现出naïve表型，它们在脐带血中数量较少。出生后，MAIT细胞获得记忆表型并急剧扩增，占血液T细胞的1%-4%。最后，与NKT细胞相比，人类MAIT细胞的发育独立于分子接头SAP。有趣的是，小鼠MAIT细胞显示naïve表型，不表达ZBTB16转录因子，相反，NKT细胞和出生后外周发现的记忆人类MAIT细胞表达ZBTB16转录因子。综上所述，MAIT细胞在胸腺非B非t造血细胞上被MR1选择，并获得记忆表型，并在依赖于B细胞和细菌菌群的过程中在外周扩增。因此，它们的发育遵循一种独特的模式，在NKT和γδ T细胞的交叉点。白细胞或淋巴细胞在保护身体免受感染和疾病方面起着重要作用。T淋巴细胞种类繁多，功能各异。mucal -associated invariant T （MAIT）细胞构成了非常规T淋巴细胞的一个子集，其特征是它们的invariant T细胞受体(TCR)α链和它们对非多态性Ib类（MHC）分子MR1的需求。MAIT细胞在人体血液和粘膜中极为丰富。与主流的T细胞相反，它们的发育需要B细胞和共生菌群。为了阐明鲜为人知的MAIT细胞，我们使用了新的工具，包括我们最近开发的用于检测人类MAIT细胞的抗体，我们能够证明MAIT细胞的发育是一个逐步的过程，胸腺内选择随后是外周扩增。我们发现胸腺选择依赖于MR1，但既不需要B细胞也不需要共生菌群，这两者都是外周扩增所必需的。与其他进化上保守的不变亚群自然杀伤T （NKT）细胞相比，我们发现MAIT细胞在成为抗原记忆细胞之前以“naïve”细胞的形式退出胸腺，并在数量上扩大，占人血液中外周T细胞的1%-4%。在小鼠中，我们发现MAIT细胞保持naïve并且没有大量扩增。我们得出结论，MAIT细胞的发育遵循一个独特的方案，其中，与NKT细胞不同，MAIT细胞的选择和扩增是由不同区室中不同细胞类型介导的非偶联事件。粘膜相关的不变T细胞是人类中最丰富的不变T细胞亚群，通过一种独特的发育途径产生，该途径代表了NKT和γδ T细胞（另外两种非常规T细胞亚群）的杂交。
Mucosal-associated invariant T (MAIT) cells display two evolutionarily conserved features: an invariant T cell receptor (TCR)α (iTCRα) chain and restriction by the nonpolymorphic class Ib major histocompatibility complex (MHC) molecule, MHC-related molecule 1 (MR1). MR1 expression on thymus epithelial cells is not necessary for MAIT cell development but their accumulation in the gut requires MR1 expressing B cells and commensal flora. MAIT cell development is poorly known, as these cells have not been found in the thymus so far. Herein, complementary human and mouse experiments using an anti-humanVα7.2 antibody and MAIT cell-specific iTCRα and TCRβ transgenic mice in different genetic backgrounds show that MAIT cell development is a stepwise process, with an intra-thymic selection followed by peripheral expansion. Mouse MAIT cells are selected in an MR1-dependent manner both in fetal thymic organ culture and in double iTCRα and TCRβ transgenic RAG knockout mice. In the latter mice, MAIT cells do not expand in the periphery unless B cells are added back by adoptive transfer, showing that B cells are not required for the initial thymic selection step but for the peripheral accumulation. In humans, contrary to natural killer T (NKT) cells, MAIT cells display a naïve phenotype in the thymus as well as in cord blood where they are in low numbers. After birth, MAIT cells acquire a memory phenotype and expand dramatically, up to 1%–4% of blood T cells. Finally, in contrast with NKT cells, human MAIT cell development is independent of the molecular adaptor SAP. Interestingly, mouse MAIT cells display a naïve phenotype and do not express the ZBTB16 transcription factor, which, in contrast, is expressed by NKT cells and the memory human MAIT cells found in the periphery after birth. In conclusion, MAIT cells are selected by MR1 in the thymus on a non-B non-T hematopoietic cell, and acquire a memory phenotype and expand in the periphery in a process dependent both upon B cells and the bacterial flora. Thus, their development follows a unique pattern at the crossroad of NKT and γδ T cells. White blood cells, or lymphocytes, play an important role in defending the body from infection and disease. T lymphocytes come in many varieties with diverse functions. Mucosal-associated invariant T (MAIT) cells constitute a subset of unconventional T lymphocytes, characterized by their invariant T cell receptor (TCR)α chain and their requirement for the nonpolymorphic class Ib (MHC) molecule, MR1. MAIT cells are extremely abundant in human blood and mucosae. Contrary to mainstream T cells, their development requires B cells and commensal microbial flora. To shed light on the little-understood MAIT cells, we used new tools, including an antibody that we recently developed to detect human MAIT cells, and we were able to show that MAIT cell development is a stepwise process, with an intra-thymic selection followed by peripheral expansion. We show that thymic selection is MR1 dependent but requires neither B cells nor the commensal flora, which are both necessary for the expansion in the periphery. In contrast with the other evolutionarily conserved invariant subset, the natural killer T (NKT) cells, we found that MAIT cells exit the thymus as “naïve” cells before becoming antigen-experienced memory cells and expanding in number to represent a significant 1%–4% of peripheral T cells in human blood. In mice, we found that MAIT cells remain naïve and do not expand substantially. We conclude that MAIT cell development follows a unique scheme, where, unlike NKT cells, MAIT cell selection and expansion are uncoupled events that are mediated by distinct cell types in different compartments. Mucosal-associated invariant T cells, the most abundant invariant T cell subset in humans, arise via a distinct developmental pathway that represents a hybrid of that seen for NKT and γδ T cells, two other unconventional T cell subsets.
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影响因子：
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作者：
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影响因子：
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幼稚CD4+ T细胞的存活中，主要的组织相容性复合物分子是否参与？
DOI：
10.1084/jem.20030963
发表时间：
2003-10-06
期刊：
The Journal of experimental medicine
影响因子：
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作者：
Grandjean I;Duban L;Bonney EA;Corcuff E;Di Santo JP;Matzinger P;Lantz O
通讯作者：
Lantz O