MR1 biochemical features and immunological functions

MR1生化特征及免疫功能

• 批准号: 7535599
• 负责人: TED Howard HANSEN
• 金额: $ 35.58万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7535599
• 关键词: Antigens; Bacteria; Biochemical; Cell Line; Cell surface; Cells; Complex; DNA Sequence Rearrangement; Development; Event; Germ-Free; Grant; Heterogeneity; Immunity; Insecta; Length; Ligand Binding; Ligands; Lymphocyte Subset; Malt Grain; Mammals; Molecular Chaperones; Mucosal Immune Responses; Mus; Mutagenesis; Nature; Peptides; Physiological; Population; Property; Protein Isoforms; Recombinants; Reporting; Surface; T-Lymphocyte; Transgenic Organisms; cytokine; frontier; in vivo; interest; receptor; trafficking

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.

描述（由申请人提供）：已提出B和T细胞上抗原特异性受体的限制性库来定义先天性免疫和适应性免疫之间边界的离散淋巴细胞亚群。这方面值得注意的例子是使用具有恒定长度的CDR 3和有限的V β区段的不变TCR链的NK-T细胞。小鼠中NK-T细胞的活化和体内发育依赖于Ib类分子CDld。最近出现了一个新的α/β T细胞群，称为粘膜相关的不变T细胞或MAlT细胞。有趣的是，MAlT细胞主要在肠道中表达，并且在无菌小鼠中缺失。此外，MAlT细胞，如NK-T细胞，具有恒定CDR 3长度的不变TCR重排和有限的Vbeta使用。最后，MAlT细胞的激活和体内发育依赖于新表征的Ib类分子MR 1。MR 1在哺乳动物中高度保守，且非MHC编码。我们最近报道，MR 1在转染的细胞系中具有有限的细胞表面表达，与肽负载复合物相关，并且经历类似于Ia类分子的配体诱导的折叠事件。此外，获得了重组MR 1，但仅在高度补充培养基中生长的昆虫细胞中获得。MR 1的这些生物化学特性和上述与CD 1的类似性，提出了一种有趣的可能性，即MR 1从肠道植物群向MAlT细胞呈递特异性配体，从而调节粘膜免疫应答。本授权中的拟议研究将定义i）内源性MR 1表达的位置，ii）MAlT细胞的效应子功能，iii）推定的MR 1配体的性质及其是否具有细菌特异性，以及iv）MR 1的MHC折叠如何与推定的配体和MAlT细胞的α/β TCR功能性相互作用。