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T-cell receptor reversal flips immunology ideology

There’s an army inside your body. Poised and prepared to do battle 24/7, your immune system’s T-cells protect you against attack from invaders such as bacteria and viruses.

But sometimes, the army rebels. Mutiny raises its ugly head. The immune system switches sides, and begins attacking the very cells it is supposed to protect.

Unfair wars like this are fought in the bodies of people with type 1 diabetes. The T-cells meant to prevent the body from attacking its own pancreatic insulin-producing cells are mostly missing in action. This leaves the cells helpless – unable to produce the level of insulin needed to regulate blood glucose levels.

There’s no cure for the disease. Type 1 diabetics face either a lifetime of injecting insulin, or a life-threatening medical emergency every time insulin levels run low. But research from the ARC Centre of Excellence in Advanced Molecular Imaging at Monash has unearthed a surprising fact about the immune response – one that may have implications for future treatments.

The immune response relies on a molecular interaction between the T-cells – a type of white blood cell – and molecules known as the major histocompatibility complex (MHC). Each T-cell has a receptor that ‘plugs-in’ to the MHC to trigger the signal that arms the immune response against invaders.

Until now, everyone thought that the T-cell receptors could only bind to the MHC in a specific way. Monash researchers have recently turned this accepted view of ‘normal’ upside-down, by making use of the equipment and expertise found at the Monash Macromolecular Crystallisation Facility (MMCF).

A team led by Professor Jamie Rossjohn has shown that unlike all previously studied receptors, the T-cell receptors associated with type 1 diabetes can bind to the MHC in the opposite orientation.

It’s a bold statement in the field of immunology. But, as part of the Monash Research Technology Platforms, the MMCF, in combination with the unique capabilities provided at the Australian Synchrotron have provided the visual proof of the pudding.

“The MMCF was essential to this work,” says Professor Rossjohn. “The automated crystallisation robotics facility enables us to be internationally competitive. Having good crystals that diffract well  speeds up data collection and processing, helping us to solve structures we haven't been able to before.”

Professor Rossjohn’s team have shown that, despite the reversed mode of connection, the T-cells can still suppress the immune system’s attacking response in the presence of insulin. In other words, even though their receptors are back-to-front, they still work. This finding challenges established views and opens up exciting opportunities for further research.

“If we can work out what part of the immune system turns rogue and how it does this, we can develop drugs that could potentially stop the immune system from completely destroying the insulin-producing cells,” Professor Rossjohn explains. “However, this would need to be done before someone develops type 1 diabetes. It won't cure people who already have it, but it could slow the process if it is diagnosed early.”