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

人体免疫系统是复杂的，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在内的各种病原体和疾病的侵害。适应性系统广泛应用T细胞，其识别由属于主要组织相容性复合体（MHC）的抗原呈递分子呈递的肽（短氨基酸聚合物）以响应检测到的病原体。其他类型的T细胞包括不变的自然杀伤T（iNKT）细胞和粘膜相关的不变T（MAIT）细胞，它们的不同之处在于它们识别由MHC样分子（如CD 1d和MR 1）呈递给它们的非肽抗原。能够结合MR 1和刺激免疫细胞的配体的确切性质仍然相对难以捉摸。已在实验室中鉴定了来自维生素生物合成途径的微生物来源的代谢产物，并且计算机筛选和体外功能测定的组合揭示了非微生物内源性配体也与MR 1结合。总之，MR 1 T细胞可以识别多种配体，然而，这些分子的确切性质仍有待充分表征。在这项研究项目中，作为伯明翰大学和生物技术公司Immunocore Ltd之间的合作，我们将：（1）开发一个综合的实验室-计算工作流程，以识别新的配体-与MR 1的自身和非自身形成的复合物;（2）将实验室-计算工作流程应用于一系列生物学研究，以识别与人类健康相关的新的生物学重要配体;（3）鉴定分离的MR 1-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.