Project: MR1T cells and altered metabolism
Our preliminary data suggest the presence of MR1T cells associated with alterred metabolism, such as during infection or autoimminity. Our team will use human peripheral blood monocyte cells (PBMCs) in combination of various microbial infection settings, to: 1) Generate and characterise infection associated MR1T cell lines; 2) Identify infection associated MR1T ligands and 3) Investigate MR1T cells in patients.
This project comprises a few sub-projects which are suitable for different levels of student enrolment. Interested student are encouraged to discuss the details with the project supervisor.
The Chen-McCluskey group is part of the MAIT cell programme headed by Prof. Jim McCluskey, with a focus on MR1-Reactive T cells (MR1T) cells.
The MAIT cell programme, also including the groups led by Dr Sidonia Eckle and Associate Professor Alexandra Corbett, has an ongoing interest on Mucosal-associated invariant T (MAIT) and MR1T cells.
MR1T cells are a recently described set of yet-to-be-defined T cells restricted by the MHC-I related protein 1 (MR1). Limited but defining evidence showed they are distinct from Mucosal-associated invariant T cells (MAIT cells): 1) They do not respond to the typical vitamin-related MAIT antigens including 5-OP-RU. Their cognate antigens are yet to be identified. 2) They do not express the canonical MAIT TCR invariant a chain (Va7.2). Instead, their TCR a and b chain usage is highly diverse. 3) They have a different cytokine profile from MAIT cells, more closely resembling conventional CD8+ cytotoxic T cells. MR1T cells are likely to be present in all individuals. However, their ontogenesis, biology and function are yet to be fully elucidated. Their seminal anticancer role reported by Crowther et al., also needs further investigation.
Since MR1 is monomorphic among individuals, the future develop of MR1T based immunotherapies, which will be applicable to all individuals (not dependent on HLA tissue type) is an extremely attractive concept, and would be advantageous compared to current conventional T cell-based immunotherapies. Towards this ultimate aim, our research projects address fundamental questions on MR1T cells, including discovering their agonist and antagonist ligands; investigating their roles in health and disease and developing immunotherapies in mouse models.
We are international leaders in MAIT and MR1T cell research, having made significant breakthrough discoveries. These include identifying the antigens recognised by MAIT cells (Kjer-Nielsen et al. Nature 2012, Corbett, Eckle, Birkinshaw, Liu et al. Nature 2014, 2 patents) and the associated development of tetramers to characterise MAIT cells (Patented) (Reantragoon, Corbett et al. JEM 2013) as well as the establishment of several mouse models of disease in order to understand the role MAIT cells play in protective and aberrant immunity (Chen et al. Mucosal Immunol 2017, Wang et al. Nature Comms 2018, Wang et al. Science Immunol 2020, Zhao et al. Nature Comms In Press). Prof. McCluskey co-authored the seminar MR1T cell paper (Crowther et al. Nat Immunol 2020), which demonstrated their anticancer role.
We have weekly lab meetings, and the three groups collaborate closely on several projects. We also share lab and management resources as well as lab and office space. Students may also be interested in other projects in the MAIT cell programme:
Links: to other groups under the MAIT cell programme.
We currently have three student projects on offer. However, interested PhD candidates are welcome to contact us at any time to discuss additional projects.