Identification and characterisation of novel ligands presented by the Major Histocompatibility Complex class I-related gene protein (MR1)

人体免疫系统很复杂，通过先天和适应性系统运作，保护人体免受包括普通感冒和COVID-19在内的多种病原体和疾病的侵害。适应性系统广泛应用T细胞识别肽（短氨基酸聚合物），这些肽由属于主要组织相容性复合体（MHC）的抗原呈递分子呈递，以对检测到的病原体做出反应。其他类型的T细胞包括不变自然杀伤T细胞（iNKT）和粘膜相关不变T细胞（MAIT），它们的不同之处在于它们识别由mhc样分子（如CD1d和MR1）呈现给它们的非肽抗原。能够结合MR1和刺激免疫细胞的配体的确切性质仍然相对难以捉摸。来自维生素生物合成途径的微生物代谢物已经在实验室中被鉴定出来，硅筛选和体外功能分析的结合表明，非微生物内源性配体也能与MR1结合。总之，MR1T细胞可以识别大量的配体，然而，这些分子的确切性质仍有待充分表征。在这个研究项目中，作为伯明翰大学和生物技术公司Immunocore Ltd的合作，我们将：(1)开发一个集成的实验室-计算工作流程来识别新的配体-包括MR1的自形成和非自形成复合物；(2)将实验室计算工作流程应用于一系列生物学研究，以确定与人类健康相关的新的和生物学上重要的配体；(3)鉴定分离的mr1抗原复合物的结构和功能。

The human immune system is complex, operates through the innate and adaptive systems and protects the human body from a wide range of pathogens and diseases including the common cold and COVID-19. The adaptive system extensively applies T cells which recognise peptides (short amino acid polymers) presented by antigen presenting molecules belonging to the Major Histocompatibility Complex (MHC) to respond to pathogens detected. Other classes of T cells, include the invariable natural killer T (iNKT) cells and mucosal-associated invariant T (MAIT) cells, which differ in the sense that they recognise non-peptide antigens presented to them by MHC-like molecules, such as CD1d and MR1. The exact nature of the ligands capable of both binding MR1 and stimulating immune cells has remained relatively elusive. Metabolites of microbial origin from vitamin biosynthetic pathways have been identified in the laboratory and a combination of in silico screening and in vitro functional assays have revealed that non-microbial endogenous ligands also bind to MR1. In summary, a wide range of ligands could be recognised by MR1T cells, however, the exact nature of these molecules remains to be fully characterised. In this research project, as a collaboration between the University of Birmingham and the biotechnology company Immunocore Ltd, we will: (1) develop an integrated laboratory-computational workflow to identify new ligands - both self and non-self- forming complexes with MR1; (2) apply the laboratory-computational workflow to a range of biological studies to identify new and biologically important ligands related to human health; and (3) characterise the structure and function of isolated MR1-antigen complexes.