Researchers at VIB, Ghent University, and VUB have uncovered how two proteins essential for immune cell development work together at the molecular level. The findings provide important insights into a critical mechanism that mediates the integration of molecular signals received from immunological threats. Their work appears in Nature Communications.

Solving a long-standing mystery in T cell biology

T cells undergo a strict selection process in the thymus before they become fully functional. This ensures that healthy T cells can recognize immunological threats while avoiding attacks against the body's own tissues. Dysregulation of this process can contribute to autoimmune diseases or immune deficiencies.

For nearly two decades, scientists have known that a protein called Themis is essential for this developmental checkpoint. However, exactly how Themis worked at the molecular level remained unclear.

Themis has always been something of an enigma. We knew it played a critical role in T cell development, but we lacked a structural understanding of how it interacts with signaling partners to carry out its function."

Dr. Danielle Clancy, first author of the study, VIB-UGent Center for Inflammation Research

The new study reveals, for the first time, the three-dimensional structure of Themis bound to Grb2, a multifunctional protein involved in numerous signaling pathways inside cells.

A dynamic signaling hub

Using cryo-electron microscopy, the researchers discovered that Themis wraps around Grb2 in an unexpectedly intricate way. At the same time, part of Grb2 remains flexible, allowing the complex to recruit other signaling proteins when T cells are activated.

"What surprised us most was how extensively Themis embraces Grb2," explains Prof. Savvas Savvides (VIB-UGent), senior author of the study.

"The interaction is much more sophisticated than anyone anticipated, involving multiple cooperative contact points that stabilize the resulting constitutive complex", adds Clancy.

The team also showed that disrupting this interaction interferes with important signaling events, confirming that the Themis-Grb2 complex is essential for proper T cell development.

"Our work provides a structural blueprint for a key signaling hub in the immune system," say Clancy and Savvides. "These insights will help us better understand how immune cells develop and may eventually support new approaches for treating immune-related diseases."