Solving a 25-year T cell conundrum

A research team from the La Trobe Institute for Molecular Science (LIMS) has solved a 25-year mystery as to how T cells are triggered when they encounter an infection or virus.

The discovery, published in Science and co-led by Professor Stephanie Gras from the La Trobe Institute for Molecular Science (in collaboration with Professor Nicole La Gruta and Professor Jamie Rossjohn from Monash Biomedicine Discovery Institute), found that T cells need to recognise pathogens in a particular order before sending an activation signal.

The immune system is our strongest line of defence against infection yet its structure is extremely complex. Multiple cells play different roles to fight infection. An important component of the immune system is killer T cells. Killer T cells (also known as CD8+ T cells) recognise infected cells and attack them, helping to fight and clear infection.

T cells have a protein on their surface called T cell receptors, or TCRs. TCRs recognise small fragments of pathogens (peptides) presented by infected cells via their Major Histocompatibility Complex (or MHC) molecules.

Since the first T cell receptor-peptide-MHC complex structure was solved by X-ray crystallography in 1996, hundreds more of these TCR-peptide-MHC structures have been determined. One common feature or characteristic of this specific interaction, and a staple of immunology textbooks, is that TCRs dock in a conservative fashion.

“This means that T cell receptors adopt a consistently recognisable docking topology, which has been observed time and time again when binding to their peptide-MHC complex,” said Dr Christopher Szeto from LIMS.

Is this just the way nature intended these molecules to come together?

“For structural biologist and immunologists alike it begged the question, what is driving such a conserved docking topology, and why?” said Professor Stephanie Gras.

This study has shown that the orientation of the T cell receptor while binding to its target (pMHC) is a critical determinant of T cell activation.

“We used a multidisciplinary approach span over multiple laboratories with biochemistry, structural biology using X-ray crystallography at the Australian Synchrotron, and mouse model of influenza infection for our in vitro and in vivo assay” said Professor Gras.

The T cell receptor is just one part of a larger and more complex system required for the activation signal to be transmitted within the cell. The researchers revealed that part of the puzzle requires the cofactors: CD8 and CD3, as well as the kinase Lck.

“TCR docking topology is a key driver to join the puzzle pieces together and ensure a successful T cell activation, which is critical for a good immune response,” said Professor Gras.

The study represented a cross-disciplinary collaboration between researchers from the University of Utah, National University of Singapore, University of New South Wales, Monash University and La Trobe University.

Read the full paper in Science titled:

Canonical T cell Receptor Docking on peptide-MHC is essential for T cell signaling.