New study reveals that "clutch" proteins are responsible for triggering T cell activation

In the context of collaborative research, scientists from three continents have been able to uncover crucial information about how T cells move their proteins to stimulate the immune response. This could help develop new specific therapies focused on T cell selectivity.

The focus of the research was on the changing composition of protein condensates in cells. Protein condensates refer to clusters formed by different types of proteins to form intracellular compartments without the need for membranes.

These condensates have been shown to play critical roles in biological pathways for both health and disease. Their roles are determined by their components and their main locations in the cell. They can thus take part in several very different processes, such as DNA replication, transmission of nerve impulses between synapses, RNA treatment and stress reactions, depending on their functions. respectively. They are also found in several cancers, in the disabling disease called amyotrophic lateral sclerosis and Huntington's disease.

3D illustration of immune system T cells attacking cancer cells (T-cell CAR therapy). Image Credit: Meletios Verras / Shutterstock

Condensates are formed during multiple interactions of molecules that can bind in multiple locations. They accumulate around one or more small molecules of proteins or RNA, like on a scaffold. The way the proteins on the scaffold, along with other proteins and scaffolds, determines the final composition of the condensate, which in turn determines its functions. This may change in response to the regulation signals, but the mechanisms are poorly understood.

One of these intracellular pathways is the activation of the immune response via T cell receptors. T cells are white blood cells concerned with cellular immunity. They recognize specific molecules called antigens on foreign particles, usually presented to the T cell pbading through an antigen presenting cell (APC). T cell binding to APC only occurs if the antigen perfectly matches the T cell receptors. This activates the rapid proliferation of the t cell, while triggering the process of producing specific antibodies. , while signaling the presence of the antigen to the rest of the body to recruit new defenses.

Current research focuses on how T cells are activated when binding to a CPA. In binding, T cell receptors initiate a cascade of protein-mediated processes called T-cell signaling complexes.

The LAT protein (linker for activation of T cells) in the cortex or at the periphery of the T cell forms a nucleus for specific condensates at the interface of APC-T cells or immunological synapse (IS) . The actin and myosin filaments in the cytoplasm form radial and concentric mobile networks in the cortex that guide the LAT condensate towards the center of the IS in order to maintain the state of activation. The question was how these two processes bind one to the other to regulate the function of activated T cells.

The researchers used two independent advances: an artificially constructed LAT condensate in vitro and an actomyosin cortical membrane in vitro. These were put together to examine how a network of actively moving actin filaments interacted with condensate. The use of the reconstructed system allowed them to bring very subtle modifications to the composition of the protein badembly, which would have been much more difficult in a living cell.

Scientists have discovered that the coupling of the T-cell signaling complex and the actomyosin cytoskeleton is done by means of two proteins called Nck and N-WASP / WASP, which introduce the LAT protein condensate into the network. Actin in different regions as needed. This allowed the network to move the condensates to the center of the cell at higher speeds. When the radial actin network gave way to a concentric network, the Nck molecule disappeared from the LAT condensate. When this loss was prevented by condensate engineering, the movement of the protein group became disordered. Thus, the cell can change the composition of the LAT condensate to move it radially towards the center of the IS. The end result was modulation of T cell receptors to stimulate immune defenses against foreign antigens.

Darius Koster, of the Warwick School of Medicine, explains: "According to the modular molecules used in LAT clusters, their interaction with actin changes. It's a bit like a clutch in your car, some molecules interact weakly with actin, but by adding another molecule, they will interact much more strongly. "

The research provides insight into how the immune response is regulated, which could lead to the development of specifically activated T cells for particular uses. The study was also unique in sharing scientific discoveries among several national groups, which made it possible to take this decisive step.

Researcher Michael Rosen said, "By living and working together for eight weeks, we have been able to make scientific discoveries that would have been impossible for any of our groups individually."

The paper was published in the newspaper eLife July 3, 2019.