A recent study has found that T cells need to recognize pathogens in a particular orientation in order to receive a strong activating signal.

The collaborative work between researchers from the University of Utah, National University of Singapore, University of New South Wales, and Monash University, is published in Science, in a paper titled, “Canonical T-cell receptor docking on peptide–MHC is essential for T-cell signaling.

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 presented by infected cells. This recognition event can lead to T-cell activation and killing of infected cells.

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 Erica Tandori (Rossjohn lab)]
“The central issue is that there are millions of different 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,” said Nicole La Gruta, PhD, professor at Monash University in Melbourne, Victoria, Australia.

“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,” La Gruta said.

More specifically, the team tested an assortment of both canonical and reversed-polarity TCRs that were all specific for the same receptor—a cognate pMHC-I bearing a peptide derived from influenza A virus (IAV). The authors determined that “docking topology was the primary driver of in vivo T-cell activation and recruitment when mice were infected with IAV.” The canonical topology, they said, was required for the formation of a functional signaling complex, suggesting that T-cell signaling constraints dictate how TCR and pMHC meet.

Pirooz Zareie, PhD, a postdoctoral research fellow at Monash University 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.”

“This is an advance in our fundamental understanding of how a T cell needs to ‘see’ pathogenic antigens in order to be activated,” La Gruta 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.”

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