By common belief in the field, it has been reasoned that T cell receptors (TCRs) must interact with each other for effective signaling. However, a new study from TU Wien and the Medical University of Viena has revealed that T cells receptors act alone. Their findings were published in Nature Immunology this week.
Johannes Huppa from the Medical University Vienna and Mario Brameshuber from TU Wien have joined forces on this project. Together, they have visualized TCRs on the surface of living T cells on a molecular level.
"Even though the mechanisms underlying T cell recognition are integral to the inner workings of the immune system, our understanding is still limited," says Huppa. This is mainly due to the fact that electron microscopes are the tool that is used to see tiny structures. However, only dead cells that are prepared for this analysis can be studied.
"A unique aspect of our joint venture is the use of specialized microscopy approaches which allow for quasi-biochemical studies on living T cells," says Brameshuber. This has been made possible by combining different techniques.
"As a biochemist, this has always been a big dream of mine, simply because this combined experimental approach allows us to study short-lived molecular processes within their native cellular context, and not in the test tube, removed from the all-defining context of life," says Huppa.
"The outer membrane of the T cell is not like a solid skin. Molecules embedded in the membrane are relentlessly on the move. This is also true for the receptors which bind to antigens—they constantly change their location," says Brameshuber. The mechanism underlying the sensitivity of T cells towards antigens was thought to depend on TCRs forming pairs or groups to signal once a TCR binds to an antigen.
According to this group of researchers, this assumption is incorrect. "Obviously the T cell receptor is a fine-tuned molecular machine, which acts as an individual entity and translates antigen-binding events into intracellular signaling with an impressive degree of processivity," says Huppa.
This work can help academic and medical researchers really understand in detail what is going on with T cells when the disease begins to develop. Hopefully, the work can contribute to the creation of precision therapies against autoimmune diseases, cancer and help avoid organ transplant rejections.
Image: Every T cell receptor of the living T cell (left) is marked with a special marker molecule. The bottom part of the cell can be imaged with a highly sensitive microscope. Image courtesy of TU Wien.