Regulation and heterogeneity of human mucosal-associated invariant T (MAIT) cells in blood and liver

Mucosal-associated invariant T (MAIT) cells are an abundant population of innate-like, effector memory T cells, that secrete proinflammatory cytokines and exhibit direct cytotoxic activity. Given their semi-invariant T cell receptor (TCR) and characteristic phenotype, MAIT cells appear as a homogeneous population. However, recent studies report some heterogeneity in surface marker expression, response to stimulation and cytokine production, as well as tissue-specific functionality. Whether such diversity reflects variable activation states, or alternatively indicates the presence of multiple transcriptionally and functionally distinct MAIT cell subsets, is currently unknown. Moreover, while the semi-invariant TCR of MAIT cells is well defined, how TCR usage varies between tissues and individuals is yet to be defined. In this thesis, I have used bulk and single-cell genomic technologies to investigate the regulation and heterogeneity of human blood and liver MAIT cells, and to explore the transcriptional response of blood MAIT cells to TCR and cytokine stimulation. In the blood, CD8+ MAIT cells exhibited a distinct transcriptional and chromatin accessibility landscape relative to CD8+ conventional memory T cells, as well as altered regulation by known and novel TFs. Single-cell RNA-sequencing indicated that human MAIT cells essentially comprise a single subset. Previously reported phenotypic heterogeneity appears to reflect differences in activation state that depend in part on both clonal origin and tissue localisation. Following TCR or cytokine stimulation, MAIT cells responded as a single population, with observed differences in functionality between cells reflecting their relative degree of activation. Lastly, I have provided an in-depth characterisation of the MAIT cell TCR repertoire and demonstrated that TCR usage is highly shared between blood and liver, but essentially unique to each individual. Overall, this study has provided fundamental insights into human MAIT cell biology and will serve as a useful foundation for studies investigating the role of MAIT cells in health and disease.