Structural Biochemistry of T-Cell Receptor Activation

ASPIRE Award (2023-Present)

Thomas Walz, PhD; Ryan Notti, MD, PhD, The Rockefeller University

Thomas Walz, PhD

Ryan Notti, MD, PhD

Immunotherapy has emerged as a powerful approach for managing advanced cancers, offering durable responses in previously treatment-resistant malignancies. However, most patients will not respond to these treatments, and many will suffer substantial toxicity, making optimization of cancer immunotherapy a pressing unmet clinical need. Signaling through the T-cell receptor (TCR) plays a central role in many immuno-oncology agents, including immune checkpoint inhibitors, adoptively transferred T cells, and bispecific T cell engagers. TCRs recognizes peptides displayed on cell surfaces by major histocompatibility complex proteins  and is essential for immune activation. However, despite decades of study and recent structural biology breakthroughs, major knowledge gaps remain in our knowledge of TCR structure and function. In particular, the role of allostery and conformational changes in TCR signaling remains controversial and their contribution to activation is an open question. These gaps have hampered efforts to improve agents which rely on TCR activation.

Recently, Tom Walz and Ryan Notti determined the structure of the TCR in the context of a native-like lipid membrane, unveiling a novel resting state of the receptor and supporting the hypothesis that conformational changes are necessary for TCR activation. Building upon this discovery, the team now proposes a series of investigations to further explore TCR structure and function. To do so, they will investigate whether conformational change is necessary for TCR function using biochemical and cellular assays, and determine the structure of the TCR in its activated state in a native-like lipid environment using cryo-electron microscopy. By delving into the conformational dynamics and functional properties of the TCR, this research holds the potential to unlock valuable insights that could enhance our understanding of TCR-mediated immune responses. These findings may guide the development of innovative strategies to modulate TCR signaling for therapeutic purposes and provide valuable insights into the influence of inherited TCR variations on cancer treatment outcomes.