CTSA News

The CCOS Communications Team interviewed researchers at the 2023 CTSA Fall Program Annual Meeting poster session in November as part of a series to feature ongoing projects across the CTSA hubs. In this article, we’re featuring Dr. Ryan Notti, KL2/K12 at Rockefeller University, who presented his work on the resting state of human T-cell receptors from the perspective of AI shortcomings and empirical insights. 

Research Question 

T-cell receptors (TCR), central to the ligand-dependent activation of T-cells, are vital in orchestrating adaptive and innate immune responses. Despite their important role, there are still major gaps in knowledge regarding the structure and function of these receptors in humans. As such, Dr. Notti and his team used cryogenic electron microscopy and in silico modeling to better understand structures of unliganded human TCR in a native-like lipid bilayer. 

Research Plan 

Dr. Notti and his team used cryogenic electron microscopy to reveal three related “closed and compacted” TCR conformations that are distinct from previously reported “extended” structures of TCR in detergent and predicted by AI. These findings underscore the importance of studying the TCR in native-like environments to correctly characterize the resting state of the receptor. The team also modeled their newly discovered TCR conformations in silico and distinguished which could accept binding from ligands, and which could not. They demonstrated that TCR-intrinsic conformational change is necessary for TCR activation.  

Next Steps 

The new TCR resting conformation reveals newly discovered biology of the receptor and has implications for the design of new T-cell targeting therapeutics. The findings open numerous doors regarding immunoreceptor engineering, allowing for structure-informed studies of patient TCR genetics and response to cancer immunotherapy. 

Reflection with the Researcher: What do you want the general public to know about the work you’re presenting here tonight?   

Dr. Notti stated that “Our ability to take pictures of molecules has drastically improved over the last decade, and these advancements will lead to better therapies for our patients in the future.”