Davey Lab research
About Dr Martin Davey
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.
1. The γδ T cell receptor repertoire in infectious disease
γδ T cells rapidly expand and correlate with protection in infectious diseases of global health importance, P. falciparum (Malaria), M. tuberculosis (TB) and cytomegalovirus (CMV). We have provided evidence that γδ T cells associated with microbial immunosurveillance undergo post-natal clonal expansion of TCR-specificities (See publications). Together, this establishes the critical requirement to identify the role γδ T cell repertoires play in human infectious disease. We are applying established state of the art TCR repertoire analysis, immunophenotyping and single cell transcriptional profiling, to reveal the molecular and cellular determinants of microbe reactive-γδ T cells in humans.
Figure 1: Human γδ T cell lineages.
We have provided significant insight into the immunobiology of human γδ T cells. Each γδ T cell population can be divided based on their Vδ chain usage. Each subset is displayed alongside a set of cell surface markers that define them in the steady state. Vγ9-/Vδ2+ and Vδ1+ γδ T cells undergo postnatal clonal selection in the periphery from a naïve γδ T cell pool. Vγ9+/Vδ2+ T cells are established in the perinatal period and are rapidly matured after birth, resulting in a uniform responsiveness to a bacterial metabolite (HMB-PP). Non-Vδ1 or Vδ2 T cells, express a Vδ3-8 TCR chain pairing and a rare fraction in the peripheral blood but are enriched in the tissues, such as the liver. We use this unique knowledge to perform cutting edge experiments, in samples from patients who have been infected by some of the world’s most challenging diseases, to inform future vaccination strategies to better protect us.
Figure 2: Clonal Expansion in the Vδ1 repertoire.
At birth, neonatal Vδ1 T cell populations are composed of a broad diverse repertoire. During the progression to adulthood, human Vδ1 T cell repertoires undergo clonotypic focussing towards a limited set of expanded TCRs. Despite this, in some individuals, clonal expansion and focussing is not evident and their Vδ1 T cell repertoires remain diverse. While human CMV infection is directly implicated in driving clonal expansion in Vδ1 T cell repertoires, other immunological stimuli are capable of driving TCR-specific responses. The TCRδ tree plots depict representative Vδ1 T cell repertoires at each stage of life. Each coloured block represents a single unique Complementarity determining region (CDR)-3δ. Each repertoire is private and clonotypes do not overlap between individuals.
2. The role of the γδ T cell repertoire in tissue immune surveillance
γδ T cells are frequently enriched in many solid tissues, however the immunobiology of such tissue-associated subsets in humans remains unclear. We have shown that intrahepatic γδ T cells are enriched for clonally expanded effector T cells, whereas naïve γδ T cells are largely excluded. Moreover, whereas a distinct proportion of circulating T cell clonotypes are present in both the liver tissue and peripheral blood, a functionally and clonotypically distinct population of liver-resident γδ T cells was also evident. Our findings suggest that factors triggering γδ T cell clonal selection and differentiation, such as infection, can drive enrichment of γδ T cells into liver tissue, allowing the development of functionally distinct tissue-restricted memory populations specialised in local hepatic immune surveillance. We are exploring the features of circulating and tissue resident γδ T cell in healthy and diseased tissue. This research program will allow us to understand how they contribute to normal homeostasis and when things go wrong, ways to help treat that situation.
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.
- Flow Cytometry
- Single cell RNAseq
- TCR repertoire sequencing
- Human immunology
We collaborate with many scientists and research organisations around the world. Some of our more significant national and international collaborators are listed below. Click on the map to see the details for each of these collaborators (dive into specific publications and outputs by clicking on the dots).
Professor Jamie Rossjohn, Monash University, Melbourne
Professor Steve Turner, Monash University, Melbourne
Professor Dale Godfrey, University of Melbourne, Melbourne
Professor Joel Ernst, UCSF, USA
Professor Katherine Kedzierska, University of Melbourne, Melbourne
Dr Peter Crompton, NIAID, USA
Dr Robert Seder, VRC NIH, USA
Dr Barry Slobedman, UNSW, Sydney
Dr Jerome Coudert, Murdoch University, Perth
Associate Professor Patricia Price, Curtin University, Perth
Dr Lucy Sullivan, University of Melbourne, Melbourne
Associate Professor Glen Westall, Monash University/Alfred Health, Melbourne
Dr Hui-Fern Koay, University of Melbourne, Melbourne
Dr Edward Giles, Monash University/Monash Health, Melbourne
Student research projects
The Davey Lab offers a variety of Honours, Masters and PhD projects for students interested in joining our group. There are also a number of short term research opportunities available.
Please visit Supervisor Connect to explore the projects currently available in our Lab.