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Congrats Phat on your first authored Nature Communications paper

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New discovery rewrites the rules of antigen presentation

Credit: Thinh-Phat Cao, Monash University.

A new discovery about how cells communicate with each other in the body’s immune system has revealed deeper insights for an international team of scientists into fundamental immune system function.

The new study, published in Nature Communications, overturns a long held understanding about how T cells – white blood cells that make up a key part of the immune system – recognise lipid antigens, a chemical class of molecules that make up cell membranes.

Lipids are presented to T cells by a distinct family of molecules called CD1, yet one member of this family, CD1c, has remained poorly understood despite its significant role in human immunity.

For more than 30 years, scientists considered that antigens were displayed to T cells in a simple, upright position, pointing directly towards the T cell. This “end-to-end” arrangement was considered a universal rule governing how immune cells recognise threats.

Now, researchers from Monash University’s Biomedicine Discovery Institute (BDI) and the Harvard-affiliated Brigham and Women’s Hospital, together with collaborators from the University of Melbourne and the University of Oxford, have challenged long-held assumptions about how immune recognition works.

Challenging rules in immunology

Using high resolution imaging the research team discovered that CD1c can display lipid molecules in an unexpected sideways orientation. Dr Adam Shahine, a NHMRC research fellow at Monash BDI, said the discovery reveals that antigen presentation is not governed by a single rigid set of rules, but instead can involve different arrangements that expand how the immune system surveys its environment.

“Much of immunology has been built around the idea that immune recognition follows one fixed arrangement,” Dr Shahine said. “This work shows that the immune system is more flexible than we assumed, and that there are additional ways immune cells can ‘see’ what’s around them.”

Rather than interfering with immune recognition, the sideways positioning allows T cells to scan CD1c effectively.

The findings show that CD1c can handle larger lipid molecules by allowing part of the molecule to extend out to the side, while remaining visible to T cells.

This new antigen display model does not merely hold for a single type of lipid. Dr Tan-Yun Cheng has demonstrated that mass spectrometry could be used to directly detect CD1c binding to dozens of lipid types, with the patterns of lipids displayed suggesting this new model could be broadly used in the CD1c system.

First author Dr Thinh-Phat Cao said that the findings highlight CD1c as a complex molecular player with unique properties in immune recognition.

“Using data collected at the ANSTO Australian Synchrotron, we found that CD1c can hold multiple lipids in place at the same time, in unique configurations, but can position them in a manner that still allows immune cells to engage,” Dr Cao said.

“That flexibility helps explain how the immune system can deal with such a wide variety of lipid molecules, shaping immune responses in unexpected ways.”

What this means for future breakthroughs on health and disease

Lipids are abundant throughout the body and play important roles in normal physiology and disease. Understanding how the immune system recognises these molecules is essential for building a more complete picture of immune function.

By revealing a new way lipids can be displayed to immune cells, the study helps explain how immune recognition can extend beyond traditional models based on proteins alone.

While this research is driven by fundamental discovery, it also lays important groundwork for future studies exploring how lipid recognition contributes to health and disease.

At Monash University, this work is supported by growing international collaborations, including through the Monash Boston Hub, which strengthens research connections between Australia and the United States.

By bringing together basic scientists and clinical researchers, these partnerships help ensure that foundational discoveries, such as this new understanding of lipid immunity, can be explored further in human disease over time.

Understanding this could lead to new strategies for diagnostics and targeted therapies.

“This discovery opens new avenues to better understand how diseases where lipids play a role,” Dr Shahine said.

“This could aid in the design of treatments that are better matched to how the body responds to disease.”

Read the full publication, “Sideways lipid presentation by the antigen-presenting molecule CD1c”, in Nature Communications: https://doi.org/10.1038/s41467-025-67732-2

This research has been supported with funding from the National Health and Medical Research Council and the Wellcome Trust.

Original article

postdoc

Congrats Adam on your Cell paper

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Researchers create “Lipidomic Map,” offering insights into immunology

An international team of scientists has developed a method for simultaneously detecting thousands of lipid molecules that are displayed to T cells in the human immune system.

The study, co-led by Professor D. Branch Moody, MD, of the Division of Rheumatology, Immunity and Inflammation at Brigham and Women’s Hospital, and Adam Shahine, PhD, at the Monash Biomedicine Discovery Institute represents a collaboration among researchers from Oxford, United Kingdom, Monash University in Melbourne, Australia and Groningen, Netherlands. The results were published today in Cell.

The team developed a new and sensitive method to detect more than 2,000 lipids bound to CD1 antigen presenting molecules, which display antigens to the human immune system.

While scientists have long known that T cells recognise antigens, until the 1990s, it was thought that these antigens were always peptides derived from proteins. Because lipids are not encoded by genes and are instead made by enzymes and form into membranes, they have entirely different functions and positions in the cell.

The ability to measure many lipid antigens at one time will allow future researchers to cross-check any disease-related lipid of interest to the list of candidate lipid antigens from this map and potentially make connections to diseases.

Their efforts yielded the first integrated CD1 lipidomic map, which could help guide the investigation and discovery of lipid blockers and antigens for T cells and support the view that lipids normally influence immune responses.

The research builds on earlier methods that separate cellular lipids in one chromatographic system, which provided only a limited perspective. The new structural biology work, undertaken by Dr Shahine, ARC DECRA fellow, showed how lipids fit inside proteins using size-based mechanisms.

Combined, the structures and biochemistry detail rules about the size, shape, and chemical content of the kinds of lipids that can bind CD1 and cause a T cell response—either activation or deactivation. It is the latest in a series of studies that date back to the 1990s, when Brigham scientists discovered that T cells can recognise lipid antigens.

“Splashdown“. The image provides a prism for thinking about how oily antigens are recognized in aqueous solution. Four lipid presenting molecules, CD1a, CD1b, CD1c and CD1d, including a three dimensional CD1-lipid complex, fall toward the surface of a blue and watery environment surrounding a T cell. Image credit: Dr Erica Tandori.

“In this ambitious decade-long, multidisciplinary study, we have characterized the full spectrum of cellular lipids that can be displayed to T cells. Further, we have collated 25 years of structural biology data, as well as new data collected at the ANSTO Australian Synchrotron, to standardize the rules that govern the molecular mechanisms in lipid presentation” said Dr Shahine. “Our hope is that the data generated in this study will serve as a foundation for future research in the field of lipid mediated immunity.”

Professor Moody said, “The Brigham provides an environment where physicians and scientists from differing fields can collaborate. This multidisciplinary effort involved biophysical techniques related to mass spectrometry and biological techniques related to lipid chemistry. The lipids informed immunological outputs, and the mode of lipid recognition is proven through X-ray crystallography.”

Read the full publication in Cell, titled CD1 lipidomes reveal lipid-binding motifs and size-based antigen-display mechanisms

DOI: 10.1016/j.cell.2023.08.022.

Original article

Congrats to our newly appointed BDI Group Leaders: Wael, Jan and Adam

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Monash BDI announce new Group Leaders

Monash Biomedicine Discovery Institute (BDI) is excited to announce 13 newly selected Group Leaders. These Group Leaders are part of a program created by Monash BDI to help early career researchers (ECRs) bridge the gap between senior postdoctoral fellow and independent lab head.

Professor Dena Lyras, Deputy Director at the Monash BDI, said that this program provides recognition and additional career momentum for researchers who are leading novel, cutting-edge research programs and developing their independence.

“Congratulations to all of the newly selected Group Leaders. This is a testament to the hard work and dedication of these researchers, and we look forward to seeing their next steps and achievements,” said Professor Lyras.

Congratulations to the newly selected Monash BDI Group Leaders:

Dr Wael Awad seeks to elucidate the mechanistic basis underpinning metabolite capture and loading of the MHC class I-related molecule “MR1” by cellular chaperones, by using cutting-edge molecular, immunological and biochemical approaches. He also explores the scope of environmental and microbial metabolites that can modulate human T cell immunity. Such studies pave the way for the development of innovative therapeutics based on selective modulation of T cell immunity.

Dr Jan Petersen’s research focuses on antimicrobial immunity and natural killer (NK) cell immunity. He investigates how T cells and NK cells recognise microbial peptide antigens presented by major histocompatibility complex (MHC) molecules, and aims to decipher the molecular mechanisms that define the ability of the adaptive immune system to distinguish between self and foreign. Focused on events central to infection and immunity, his work is aimed at understanding outcomes in various diseases and transplantation.

Dr Adam Shahine is focused on the molecular roles of lipids in the regulation and dysregulation of human adaptive immunity. Using structural biology, he seeks to investigate the mechanisms of lipid antigen recycling, and the presentation of lipid antigens by CD1 antigen presenting molecule family T cells.

Dr Deepak Adhikari aims to gain a better understanding of how mitochondria are formed and how they regulate the development of eggs and offspring.

Dr Asolina Braun aims to understand what initially causes psoriasis and hence to discover new treatments for this skin disease. Her research is focused on finding peptides that trigger and set off the detrimental immune response in psoriasis.

Dr Luke Formosa investigates how mitochondrial enzymes are built from their individual subunits, and how this process is disrupted in mitochondrial disease. One in 5,000 children will develop a mitochondrial disease, but about one-third of patients won’t have a genetic diagnosis. By discovering new genes that play a role in this process, the diagnosis of patients can be improved, paving the way for new treatments for this disease.

Dr Meiling Han’s research targets antibiotic resistance, focusing on the mechanism(s) underpinning the extensive membrane remodelling that occurs in Gram-negative bacteria and the interactions between remodelled bacterial membranes and membrane-targeting antimicrobials (e.g. lipopeptides). The fundamental mechanistic information that she generates will greatly inform the future design of much-needed antibiotics against antibiotic-resistant bacteria.

Dr Anja Knaupp’s research centres on characterising cell-type-specific sets of proteins and determining how they operate. Insight into these molecular mechanisms and drivers is key for our understanding of cellular identity and changes that, for example, occur during cancer development.

Dr Rachael Lappan aims to understand the nature and basis of microbial life in the atmosphere, the largest but most unexplored potential ecosystem on Earth. Using cutting-edge molecular and biogeochemical approaches, she aims to identify true microbial residents of the atmosphere, understand their mechanisms for survival in this environment and explore their role in seeding newly formed environments.

Dr Kate McArthur’s research uses a variety of microscopy and cell biology techniques to understand the mechanisms behind, and immune responses to, mitochondrial changes and aberrant cell death during disease.

Dr Nitin Patil is investigating peptide- and oligonucleotide-based antimicrobial drug development and delivery.

Dr Francesca Short combines genomic and molecular microbiology approaches to understand bacterial behaviour and adaptation. Her current research focuses on how bacteria control the production of virulence factors during infection and on how common disinfectants can compromise antibiotic efficacy.

Dr Yogitha Srikhanta investigates strategies that bacterial gut pathogens employ to proliferate, cause disease and survive, with a focus on antibiotic resistance and epigenetic-mediated gene regulation.

Original article