Dr Martin Davey gained his PhD (2013) in the group of Professor Bernhard Moser and Dr Matthias Eberl at Cardiff University, exploring the responses of human γδ T cells towards multi-drug resistant bacterial pathogens, in concert with monocytes and neutrophils. He then undertook postdoctoral research training in the group of Professor Ben Willcox at the University of Birmingham, UK. There he employed T cell receptor (TCR) deep sequencing and single cell methodology to explore the underlying biology of this enigmatic T cell population, revealing an alternative immunobiology that governs a large population of human γδ T cells. He joined Monash University’s Biomedicine Discovery Institute in June 2018 and has established the immune surveillance laboratory to explore the role of γδ T cells in microbial infections and tissue immune surveillance.
Human unconventional T cells represent >20% of all T cells in the periphery and are frequently implicated in anti-bacterial, anti-viral and anti-parasitic immunity. Yet, the mechanisms that this group of immune cells employs to communicate and control these states of infection is unclear. The exposures we face throughout life shape our unconventional T cell compartment into a pool of resident and circulating sentinels poised to engage diverse antigenic stimuli. These challenges shape the immune surveillance network these enigmatic T cells form in the periphery. Knowledge of this arm of immunity will allow us to develop vaccine strategies to promote better protection against infectious disease and cancer. Our research uses cutting-edge immunological techniques on human samples from bacterial (tuberculosis), viral (cytomegalovirus) and parasite (malaria) infected patients to unravel the immunobiology of human γδ T cells and MAIT cells.
Figure 3: Tissue immune surveillance by the γδ T cell repertoire.
Both γδ Tnaïve and Teffector cells circulate in the peripheral blood. γδ Tnaïve populations (expressing CCR7 and CD62L) are likely to migrate to secondary lymphoid tissue, via CCL19 and CCL21 chemokine gradients. Access to secondary lymphoid tissue permits encounter of homeostatic interleukin 7 (IL-7), maintaining γδ Tnaïve cells and allowing their persistence throughout adulthood. γδ Tnaïvecells may also encounter cognate antigen either in the lymphoid tissues, akin to αβ T cells, or elsewhere, and give rise to γδ Teffector cells. Circulating γδ Teffector populations may enter peripheral tissues, accessing homeostatic IL-15 concentrations. Access to peripheral tissues may indicate a stress surveillance role and antimicrobial function, through T cell receptor (TCR)–ligand engagement.
Figure 4: Human liver infiltrating γδ T cells are composed of clonally expanded circulating and tissue-resident populations.
The ability of γδ T cells to undergo clonotypic expansion and differentiation is crucial in permitting access to solid tissues, such as the liver, which results in functionally distinct peripheral and liver-resident memory γδ T cell subsets. They also highlight the inherent functional plasticity within the γδ T cell compartment and provide information that could be used for the design of cellular therapies that suppress liver inflammation or combat liver cancer.
3. MAIT cell function (led by Dr Lauren Howson)
MR1-restricted mucosal-associated invariant T (MAIT) cells recognize vitamin B metabolites, which are generated by a broad range of bacteria, from Escherichia coli to Mycobacterium tuberculosis and BCG. MAIT cells are innate sensors of infection and they accumulate early in infected tissues. MAIT cells maintain an activated phenotype throughout the course of infections, secrete inflammatory cytokines, and have the potential to directly kill infected cells, playing an important role in shaping the host response. We are using cutting edge techniques, in vitro assays and patient samples to explore the mechanisms that control this unconventional T cell populations contribution to immune surveillance.
Figure 5: MAIT cell activation in infection and sterile disease.
Bacteria or yeast can stimulate MAIT cell activation following infection or phagocytosis by antigen presenting cells. These cells can then present microbial-derived vitamin B metabolites via MR1 (associated with β2-microglobulin) to the Vα7.2-bearing MAIT TCR. Upon infection, antigen presenting cells also produce IL-12 and IL-18 cytokines that can activate MAIT cells in an antigen-independent mechanism. The production of IL-7 from hepatocytes can act synergistically to enhance MAIT cell activation. Viruses can stimulate MAIT cells through detection of their molecular patterns by pattern recognition receptors, such as ssRNA by TLR8 on antigen presenting cells, resulting in the production of IL-12 and IL-18. In sterile disease, such as autoimmunity, cells that pathologically express cytokines IL-12 and IL-18 can activate MAIT cells. The activation of MAIT cells results in the production of Th1 cytokines IFNγ and TNFα, Th17 cytokines IL-17 and IL-22 (particularly by small intestine-derived MAIT cells), and release of perforin and granzyme B to directly kill infected cells.