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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

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Congrats Mohamed on your first authored JEM paper

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Scientists discover natural molecules that help calm immune cells

First author on the JEM publication, Monash BDI PhD student Mohamed Abdelaal, and co-senior and co-corresponding author, Dr. Wael Awad.

Researchers have uncovered a surprising way the human body helps keep its immune system in check. The study found that when the body breaks down vitamin B2 (riboflavin), it produces natural molecules that can reduce the activity of MAIT cells – specialised immune cells involved in inflammation.

Co-led by Monash Biomedicine Discovery Institute (BDI) and University of Melbourne researchers, and published in the Journal of Experimental Medicine, the discovery shows that our bodies naturally produce molecules that can suppress MAIT cell activity, filling a major gap in understanding how the body maintains immune balance. Previously, research focused on how bacteria activate these cells, but little was known about the body’s own regulatory mechanisms.

These molecules interact with an immune sensor called MR1, which normally helps activate MAIT cells. Instead of boosting MR1 activity like vitamin-related molecules do, the body’s own molecules keep MR1 inside the cell, lowering its presence on the surface and dampening the immune response.

“Our findings reveal a natural mechanism that prevents unnecessary immune activation and inflammation,” said Mohamed Abdelaal, a PhD student with the Monash BDI and first author of the study.

“Understanding this process opens the door to new ways of controlling inflammation and immune-related diseases, by targeting overactive immune responses,” he said.

The study highlights a new dimension of MR1 biology and its role in immune homeostasis, paving the way for future research into how metabolic byproducts influence immunity.

Next steps include testing these molecules in living systems and exploring drug-like compounds that fine-tune MAIT cell activity, potentially leading to new therapeutic targets for immune disorders.

This study was co-led by Dr Wael Awad from Monash University’s Biomedicine Discovery Institute, and Dr Nicholas Gheradin from the Peter Doherty Institute for Infection and Immunity, University of Melbourne.

Read the full paper published in the Journal of Experimental Medicine, titled The antigen presenting molecule MR1 binds host-generated riboflavin catabolites.
DOI: 10.1084/jem.20250711

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