THEME 7 IMAGING METABOLITE MEDIATED IMMUNITY

Artwork of a gamma delta T cell receptor interacting with MR1
Dr Erica Tandori, artist in residence from the Rossjohn Laboratory at Monash University.

“We obtained a detailed 3D image of the interplay between the gamma delta T cell receptor and MR1 revealing an intriguing result whereby the gamma delta T cell receptor bound underneath the MHC-like molecule for recognition. This highly unusual recognition mechanism reshapes our understanding of how T cell receptors can interact with their target molecules and represents a major development in the field of T cell biology”

In 2012 and 2014, Imaging CoE scientists made the startling discovery that an abundant T cell population, termed mucosal-associated invariant T (MAIT) cells were activated by metabolites of vitamin B2 (called riboflavin) (Nature 2012 & 2014).

Armed with this information, the field is now empowered to identify and understand the roles of MAIT cells in mammalian homeostasis, health and disease. To further enable this, Imaging CoE scientists have developed novel biochemical reagents (MR1 tetramer proteins, MR1-binding fluorescent ligands, MAIT cell-binding fluorescent ligands) that have enabled the identification, tracking, and phenotypic characterisation of antigens, their initial target MR1 on antigen presenting cells, and their eventual target MAIT cells that have important immunoregulatory properties in mammals.

PROF. JAMIE ROSSJOHN
PROF. DALE GODFREY
PROF. DAVID FAIRLIE

AT A GLANCE

Work in this area has helped establish:

  1. The revelation that the gamma delta T cell receptor can recognise and interact from underneath MR1. This highly unusual recognition mechanism reshapes our understanding of how T cell receptors can interact with their target molecules and represents a major development in the field of T cell biology (Le Nours et al. Science 2019).
  2. Understanding mechanisms of IL-23 costimulation on MAIT cell activation (Wang et al., Science Immunology 2019).
  3. Unambiguous characterisation of human and mouse MAIT cells (Curr Protoc Immunol. 2019).
  4. The divergent transcriptional landscape that underpins development and functional branching of MAIT cells (Science Immunology 2019).
  5. The chemical components of the bacterial antigen that activates MAIT cells (Chemistry 2019).
  6. Effects of Legionella on the type and populations of MAIT cells in the lung (Nat Comm 2019).
  7. MAIT cell responses to immunodeficiency viruses (J Immunol 2019).
  8. Identification of new types of MR1-restricted T cells that do not express an invariant TCR-a chain. (Koay et al. 2019. Nat Commun).
  9. That MAIT cells can also produce Th2-type cytokines involved in immune regulation. (Kelly et al. 2019. Immunol Cell Biol).
  10. The changing transcriptional landscape that is associated with the development of MAIT cells (Koay et al. 2019 Sci Immunol).

ACTIVITY PLAN

  1. Continue investigations into MAIT cell antigen recognition and activation.
  2. Continue investigations into MR1-restricted T cell antigen recognition, activation and homeostasis.
  3. Determine crystal structures for antigen-MR1 binary complexes.
  4. Develop a binding assay for optimising antigen-MR1 affinities.
  5. Design and develop inhibitors of MAIT cell activation.
  6. Probe the mechanisms of antigen presentation and MR1 trafficking.
  7. Assess the immunological impacts of MAIT activation in vitro and in vivo.

HIGHLIGHT

Advanced imaging tips t cell target recognition on its head

T cells represent a key component of our immune system and play a critical role in protecting us against harmful pathogens like viruses and bacteria, and cancers. The more we understand about how they recognise, interact with and even kill infected or cancer cells moves us closer to developing therapies and treatments for a range of conditions.

In a paper published in the premier international journal Science, an Australian team of scientists led by the Imaging CoE at Monash University and the Peter Doherty Institute for Infection and Immunity at the University of Melbourne have redefined what we thought we knew about T cell recognition for the past 20 years.

In order to interact with other cells in the body, T cells rely on specialised receptors known as T cell receptors that recognise virus or bacteria fragments that are bound to specialised molecules called major histocompatibility complex (MHC) or MHC-like. Over the past 20 years, the prevailing view was that T cell receptor sat atop the MHC and MHC-like molecules for recognition.

The team of scientists characterised a new population within a poorly understood class of T cells called gamma delta T cells that can recognise an MHC-like molecule known as MR1. Using a high-intensity X-ray beam at the Australian Synchrotron, the scientists obtained a detailed 3D image of the interplay between the gamma delta T cell receptor and MR1 revealing an intriguing result whereby the gamma delta T cell receptor bound underneath the MHC-like molecule for recognition. This highly unusual recognition mechanism reshapes our understanding of how T cell receptors can interact with their target molecules, and represents a major development in the field of T cell biology.

“Think of it like a flag attached to a cell. We always thought the T cells were coming along and reading that flag by sitting atop it. We have determined that instead, some T cells can approach and interact with it from underneath,” said Dr Jérôme Le Nours from the Monash Biomedicine Discovery Institute, co-lead author on the paper.

“These are the types of fine and important details that can change how we approach future research avenues in T cell biology,” said Dr Le Nours.

“This is important because T cells are a critical weapon in our immune system, and understanding how they target and interact with cells is crucial to harnessing their power in therapies such as infection and cancer immunotherapy,” he said.

”Our study shows that MR1 is a new type of molecular target for gamma delta T cells. These cells play a decisive role in immunity to infection and cancer, yet what they respond to is poorly understood. MR1 may be signalling to gamma delta T cells that there is a virus or cancer cell and triggering these cells to initiate a protective immune response,” said Dr Nicholas Gherardin from the Doherty Institute, co-lead author on the paper.

“We’re very excited to follow up these findings in studies that will aim to harness this new biology in disease settings,” he said.

The research findings were a culmination of a six-year project that involved collaborative support from Australian scientists, the Imaging CoE, the use of the Australian Synchrotron, and funding from the National Health and Medical Research Council and the Australian Research Council.

Read the full paper in Science titled A class of γδ T cell receptors recognize the underside of the antigen-presenting molecule MR1

Artwork of a gamma delta T cell receptor interacting with MR1

Credit: Dr Erica Tandori, artist in residence – Rossjohn Laboratory at Monash University.

ACHIEVEMENT

Defining the basis of unconventional immune cell development

Dr Martin Davey, a Monash Biomedicine Discovery Institute (BDI) researcher from Professor Jamie Rossjohn’s lab, received an Australian Research Council (ARC) Discovery Early Career Researcher Award (DECRA). The DECRA scheme supports research in areas of critical national importance by enabling outstanding Australian and international early career researchers to conduct their research in Australia.

Dr Davey will receive more than $425,000 for his research project titled ‘Defining the basis of unconventional immune cell development’. With this funding, he aims to undertake discovery research to characterise the transcriptional programs that underpin the development of unconventional immune cells.

Unconventional T lymphocytes are a poorly understood component of the immune system but emerge very early in mammalian life. T cells are defined by their expression of a T cell receptor (TCR), however, while the majority express diverse ab TCRs (‘conventional’), the remaining cells express either an alternative γδ TCR or a highly constrained ab TCR (‘unconventional’). The study of the developmental origins of human unconventional immune cells is an emerging and important area of basic research and discovery.

“The development of the immune system in early life is now thought to be critical to our response to immune challenges in adulthood, such as microbial infections. I aim to generate new knowledge in this area by using cutting-edge transcriptome analysis and cellular immunophenotyping at the single-cell level to examine the seeding of unconventional immune cells,” Dr Davey said.

“This project aims to advance our understanding of immune cell biology and the programs that control them, while significantly strengthening national excellence in unconventional immune cell research and providing innovative methodology,” he said.

Article source:
Monash University, Monash Biomedicine Discovery Institute

Dr Martin Davey.