Mucosal associated invariant T cells: mechanisms of bacterial control in humans
Mucosal associated invariant T (MAIT) cells are an unconventional T cell subset that are abundant in humans in blood, liver, and mucosal tissues. MAIT cells express a semi-invariant T cell receptor (TCR) (Vα7.2-Jα12/20/33) and are restricted to antigen presented by the non-polymorphic, evolutionarily conserved MHC class IB molecule, MHC class I related protein (MR1). MR1 presents unstable pyrimidine derivatives of a metabolic precursor of microbial riboflavin synthesis, and trigger MAIT cell activation via their TCR. Like other unconventional T cells, MAIT cells express cytokine receptors, such as interleukin (IL)-12R and IL-18R, at high levels and can respond to cytokines, produced during bacterial or viral infections, independently of TCR stimulation. As a result, MAIT cells may play a role in infection by a broad range of bacteria, fungi, and viruses, as well as in sterile inflammation. Activation via the two modes can occur independently or simultaneously, depending upon the stimuli. However, it is unclear whether the effector functions of human MAIT cells differ by mode of activation. Therefore, this study compared functional and genome wide transcriptional responses of blood and liver derived MAIT cells to riboflavin-producing bacteria (Escherichia coli), soluble pyrimidine ligands, and cytokines (IL-12+IL-18) to define the full array of effector functions. TCR stimulation of both blood and liver derived MAIT cells triggered rapid acquisition of a polyfunctional proinflammatory phenotype, with the expression of multiple cytokines and chemokines, while the response to cytokine activation was slower and narrower. In TCR activated MAIT cells, there was also enrichment of a tissue repair gene expression signature, indicating a potential homeostatic role for MAIT cells. Of note, the functional and genome-wide response of both blood and liver derived MAIT cells was strikingly similar. While liver-derived MAIT cells were more responsive to cytokine stimulation, there was no significant difference in the response to TCR stimulation between blood and liver-derived MAIT cells. When the transcriptome of unstimulated blood and liver-derived MAIT cells were compared, there was no substantial difference in the circulatory and tissue residency gene expression signatures, suggesting that MAIT cells may recirculate between blood and liver. Both commensals and pathogens synthesise riboflavin and could activate MAIT cells that are abundant in liver and in mucosal tissues, therefore their activation must be regulated to prevent immunopathology. Therefore, this study further explored the bacterial signals and the co-stimulatory molecules that they induce that are important in regulating TCR-mediated MAIT cell activation. Type I interferons were identified as a major regulatory signal that can directly activate MAIT cells as well as enhancing the response of MAIT cells to TCR activation. Furthermore, intact ligand deficient bacteria enhanced MAIT cell activation by pyrimidine ligand to a greater extent than lysed bacteria or TLR agonists, suggesting the physiological form of bacteria is essential to trigger robust MAIT cell activation. Overall, this study has significantly advanced our knowledge of MAIT immunobiology, highlighting differences in the response of MAIT cells to TCR and cytokine signals. The regulation of TCR responses by innate signals, which are abundantly present during bacterial infection, suggests a regulatory mechanism to prevent inappropriate activation and immunopathology.
Advisor: Ussher, James; Kirman, Joanna
Degree Name: Doctor of Philosophy
Degree Discipline: Department of Microbiology and Immunology
Publisher: University of Otago
Keywords: MAIT cells; Activation; Effector functions; RNA sequencing; Transcriptome; Type I interferons; Interleukin-12/18; 5-A-RU/5-OP-RU; Bacterial signals; Blood; Liver
Research Type: Thesis