Monash University researchers have provided a fundamental advance regarding how T cells become activated when encountering pathogens such as viruses.
The recent study published in Science, co-led by Professor Nicole La Gruta, Professor Jamie Rossjohn and Professor Stephanie Gras with first author Dr Pirooz Zareie from the Monash Biomedicine Discovery Institute, have found that T Cells need to recognise pathogens in a particular orientation in order to receive a strong activating signal.
T cells play a key role in the immune system by eliminating invading pathogens, such as viruses, and it is crucial to understand the factors that determine how and why T cells become activated after recognizing these pathogens.
T cells express on their surface a T cell receptor (TCR) that recognizes and binds to virus fragments (antigens) presented by infected cells. This recognition event can lead to T cell activation and killing of infected cells.
“The central issue is that there are millions of different T cell receptors (TCRs) in the human body, and a vast array of viruses, making it difficult to understand the rules around how T cell receptor recognition of a virus drives T cell activation. Indeed, it is a problem that has remained contentious for over 25 years” says Professor La Gruta.
“Our study has shown that the orientation in which the T cell receptor binds is a primary factor determining whether the T cell receives an activating signal,” Professor La Gruta said.
“This is an advance in our fundamental understanding of how a T cell needs to ‘see’ pathogenic antigens in order to be activated,” she said. “It has clarified a critical mechanism essential for effective T cell immunity. It is also relevant to the ongoing development of immunotherapies that aim to boost the activation of T cells.”
Dr Pirooz Zareie stated: “a combination of technologies, including super-resolution microscopy, X-ray crystallography at the Australian Synchrotron, biochemical assays and using in vitro and in vivo experimental models from a variety of labs led to the findings.”
The study represented a cross-disciplinary collaboration between researchers from the University of Utah, National University of Singapore, University of New South Wales and Monash University.
TCR-pMHC recognition – through the looking glass. The image shows a brightly colored canonical interaction between TCR and pMHC which is conducive to signal transduction. The faded mirror image shows a reversed TCR-pMHC interaction which is unable to support signal transduction and thus T cell activation. (Created by Dr. Erica Tandori, Rossjohn lab)
Read the full paper in Science titled: Canonical T cell Receptor Docking on peptide-MHC is essential for T cell signaling.DOI: 10.1126/science.abe9124
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