MR1 biochemical features and immunological functions

描述(由申请人提供)：B和T细胞上抗原特异性受体的限制性谱系已被提出用来定义天然免疫和获得性免疫之间的离散淋巴细胞亚群。值得注意的例子是NK-T细胞使用恒定长度的CDR3和有限的Vbeta片段的不变(TCR链)。小鼠NK-T细胞的激活和体内发育依赖于Ib类分子CDLD。最近出现了一个值得注意的故事，即一种新的α/βT细胞群体，称为粘膜相关不变T细胞或MALT细胞。有趣的是，MALT细胞主要在肠道中表达，在无菌小鼠中缺失。此外，MALT细胞和NK-T细胞一样，具有恒定CDR3长度和有限的Vbeta使用的不变(TCR)重排。最后，MALT细胞的激活和体内发育依赖于新鉴定的Ib类分子MR1。MR1在哺乳动物中高度保守，非MHC编码。我们最近报道，MR1在转基因细胞系中具有有限的细胞表面表达，与多肽负载复合体相关，并经历类似于la类分子的配体诱导的折叠事件。此外，获得了重组的MR1，但仅在高度添加的培养基中生长的昆虫细胞中获得。MR1的这些生化特性以及上述与CD1的类似物，提高了MR1提供从共生菌群到MALT细胞的特定配体的有趣可能性，从而调节粘膜免疫反应。这项赠款中建议的研究将定义：i)内源性MR1在哪里表达，ii)MALT细胞的效应功能，iii)假定的MR1配体的性质以及它是否是细菌特异性的，以及iv)MR1的MHC折叠如何与假定的配体和MALT细胞的α/βTCR功能相互作用。

DESCRIPTION (provided by applicant): Restricted repertoires of antigen specific receptors on B and T cells have been proposed to define discrete lymphocyte subpopulations at the frontier between innate and adaptive immunity. Notable examples of this are NK-T cells that use an invariant (TCR chain with a CDR3 of constant length and limited Vbeta segments. The activation and in vivo development of NK-T cells in mice is dependent upon the class Ib molecule, CDld. A remarkable story has recently emerged of a new alpha/beta T population termed mucosal-associated invariant T cells or MAlT cells. Interestingly, MAlT cells are predominantly expressed in the gut and are missing in germ-free mice. Furthermore, MAlT cells, like NK-T cells, have an invariant (TCR rearrangement of constant CDR3 length and limited Vbeta usage. And finally, activation and in vivo development of MAlT cells is dependent upon the newly characterized class Ib molecule, MR1. MR1 is highly conserved among mammals, and non-MHC encoded. We recently reported that MR1 has limited cell surface expression in transfected cell lines, is associated with the peptide-loading complex, and undergoes a ligand induced folding event similar to class la molecules. Furthermore, recombinant MR1 was obtained, but only in insect cells grown in highly supplemented media. These biochemical properties of MR1and the aforementioned analogies with CD1, raise the interesting possibility that MR1 presents a specific ligand from commensal flora to MAlT cells and thereby regulates mucosal immune responses. The proposed studies in this grant will define i) where endogenous MR1 is expressed, ii)the effector function of MAlT cells, iii) the nature of the putative MR1 ligand and whether it is bacteria-specific, and iv) how the MHC fold of MR1 functionally interacts with a putative ligand and the alpha/beta TCR of MAlT cells.