Unconventional functions of MR1 restricted T-cells

Thesis

The non-polymorphic MHC class I-related protein 1 (MR1) is an antigen presenting receptor that displays endogenous or microbial-derived metabolic intermediates. The commensal antigens, such as intermediates of the riboflavin synthesis pathway, are the most well understood so far and, these are known to activate mucosal associated invariant T (MAIT) cells. MAIT cells have been widely studied for their innate-like properties and, their strong pro-inflammatory and anti-microbial functions in response to TCR-dependent and TCR-independent signalling. These characteristics confers them with an important, but so far unclear, role in mucosal immunity and autoimmune diseases. Other non-MAIT MR1-restricted T (MR1T) cells have shown specificity to both commensal and endogenous antigens; however, we are still far from understanding the diversity in their functions, phenotype, antigenic specificity and, TCR repertoire.

In this thesis, we used RNAseq analysis to dissect the downstream effects of TCR-dependent and TCR-independent signals on their own and in combination. Our experiments revealed that while the inflammatory responses are tightly regulated and primarily driven by TCR-independent signalling, TCR-mediated activation elicit other unexpected functions related to homeostasis and tissue repair. These data provide a deeper insight on how MAIT cells balance inflammatory and protective functions at barrier sites under constant exposure to the microbiota.

We also explored MR1 as a target molecule for TCR-based immunotherapy against cancer disease. We hypothesised that the endogenous metabolic intermediates could be antigens of interest for the specific targeting of cells undergoing metabolic stress, such as transformed cancerous cells. In this thesis, we collaborated with Immunocore, a leader in TCR-based immunotherapies, to validate the role of MR1T cells in cancer disease and analysed the specificity of 2 new autoreactive MR1T cells. This work also proposes new methods to accelerate the discovery of antigens and TCR sequences in the unexplored field of MR1T cells.

Authors: Delowar Akther, H

• DOI: 10.5287/ora-v0ye62jje
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: cancer immunotherapy; endogenous antigens; regulatory functions of MAIT cells; MR1 restricted T-cells; tissue repair functions of MAIT cells; mucosal associated invariant T-cells; MR1; MAIT; MR1 based immunotherpay; MR1T
• Subjects: Tissue repair functions of MAIT cells; Immunoregulatory functions of MAIT cells; Ex-vivo detection of MR1T cells; Discovery of MR1-specific T-cells reactive to cancer antigens