By uncovering an enduring mystery around how activation signals are modulated in immune cells, scientist find a potential guide to designing more effective immune therapies
 

An international team of researchers reveal a mechanism by which signalling molecules interact to generate a robust immune response, that simultaneously allows the attack signal to be quickly switched off when needed.

Once a T cell detects a foreign particle, via the T cell receptor, it is spurred into protective mode. This is when important signalling proteins, like ZAP70, are recruited to the T cell receptor to promote and amplify the immune response. Strong signals are crucial to mounting a robust immune response, and they rely on sustained binding of ZAP70 to the T cell receptor – the longer lasting the interaction, the more potent the response.

To ensure protection is achieved, T cells need to be highly responsive to even the smallest signs of danger, while ignoring the multitude of weak signals it encounters – like from surrounding healthy tissues – that elicit short-lived ZAP70 binding.

T cell researchers have wondered how proteins with tandem binding domains, like ZAP70, achieve the dual properties of long-lasting contact and access for rapid disconnection.

“You can’t have it both ways, unless there is some clever mechanism, such as the one we describe in this work,” said Dr Jesse Goyette of the EMBL Australia Node in Single Molecule Science, one of the co-leads of the study published in the journal, Proceedings of the National Academy of Sciences USA.

“The question is, how can we have a good specific interaction between these adaptor proteins and their targets, but also be able to shut it off quickly. An underappreciated aspect of these pathways is how they are reversed,” he said.

Using mathematical modelling and experimental validation, the team co-led by researchers from UNSW Medicine & Health and Oxford University shows that ZAP70 binds to the T cell receptor in a dynamic way, and this is the key to the responsiveness to changing circumstances in the microenvironment.

“It allows you to better explain why T cells are able to ignore self-antigens and react to foreign antigens,” Dr Goyette said about this finding.

The researchers dubbed ZAP70 the “tiny dancer” because of the movement of this protein observed with live cell imaging. The protein’s tandem binding domains are like a dancer’s two feet.

 Microscopy image of lactating mammary gland tissue by Krystyna Gieniec; Copyright 2022 BBA Molecular Cell Research, Elsevier