|Title||The structural basis of T cell receptor (TCR) activation: An enduring enigma.|
|Publication Type||Journal Article|
|Year of Publication||2019|
|Authors||Mariuzza, RA, Agnihotri, P, Orban, J|
|Journal||J Biol Chem|
|Date Published||2019 12 17|
T cells are critical for protective immune responses to pathogens and tumors. The T cell receptor (TCR)-CD3 complex is composed of a diverse ab TCR heterodimer noncovalently associated with the invariant CD3 dimers CD3epsilon/gamma, CD3epsilon/delta, and CD3zeta/zeta. The TCR mediates recognition of antigenic peptides bound to MHC molecules (pMHC), while the CD3 molecules transduce activation signals to the T cell. Whereas much is known about downstream T cell signaling pathways, the mechanism whereby TCR engagement by pMHC is first communicated to the CD3 signaling apparatus, a process termed early T cell activation, remains largely a mystery. In this review, we examine the molecular basis for TCR activation in light of the recently determined cryoEM structure of a complete TCR-CD3 complex. This structure provides an unprecedented opportunity to assess various signaling models that have been proposed for the TCR. We review evidence from single-molecule and structural studies for force-induced conformational changes in the TCR-CD3 complex, for dynamically driven TCR allostery, and for pMHC-induced structural changes in the transmembrane and cytoplasmic regions of CD3 subunits. We identify major knowledge gaps that must be filled in order to arrive at a comprehensive model of TCR activation that explains, at the molecular level, how pMHC-specific information is transmitted across the T cell membrane to initiate intracellular signaling. An in-depth understanding of this process will accelerate the rational design of immunotherapeutic agents targeting the TCR-CD3 complex.
|Alternate Journal||J. Biol. Chem.|