T cell receptor signal transduction: affinity, force and conformational change

T cell recognition of antigen and resulting proximal signaling are key steps in the initiation of the adaptive immune response. The T cell receptor interaction with antigen drives signal initiation in an affinity-dependent manner, but many aspects of this process remain incompletely understood, including what regions are responsible for structural changes in the TCR upon antigen binding, the importance of extracellular T cell receptor interactions with CD3, how structural changes are integrated with signaling components, and the role of force in signal transduction. Advances in structural modeling of the TCR–CD3 complex and the ability to quantify the affinity and biophysical nature of these molecular interactions have significantly furthered our understanding of the mechanism of transduction of T cell antigen recognition into intracellular signaling. This knowledge is paramount to understanding how T cell perform their critical role in adaptive immune responses, and for the development and improvement of immunotherapies.