New research provides mechanistic insight into tuning of immune responses

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. 

| 25 Feb 2022

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.

“It gives you a mental image of the domains bouncing around like they are dancing on these binding sites, which is how we image how this happens,” said Dr Goyette.

Having two binding domains side by side increases the affinity of the protein binding, but the dynamic binding state allows specialist molecules – called phosphatases – to come in and unbind ZAP70, short circuiting the signals. Access would be unavailable for phosphatases if ZAP70 interacted with the T cell receptor in a static mode, where both binding domains were constantly engaged to the binding sites.  

Dr Goyette suggests that understanding this mechanism could inform the designs for new immunotherapies, like chimeric antigen receptor (CAR) T-cell therapy, where immune receptors on the patient’s own T cells are re-configured to specifically detect and attack cancers before they are reinfused into their circulation.

“It would improve our ability to engineer better constructs of CAR T-cell therapies,” he said.