The structural basis of T-cell receptor (TCR) activation: An enduring enigma

Abstract

T cells are critical for protective immune responses to pathogens and tumors. The T-cell receptor (TCR)–CD3 complex is composed of a diverse αβ TCR heterodimer noncovalently associated with the invariant CD3 dimers CD3ϵγ, CD3ϵδ, and CD3ζζ. The TCR mediates recognition of antigenic peptides bound to MHC molecules (pMHC), whereas 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.

T Cell Activation Machinery: Form and Function in Natural and Engineered Immune Receptors

“…The cytoplasmic tails were not resolved in the cryo-EM structure [ 1 ], consistent with what we know about their lack of stable structure and their dynamic interactions with lipids and signaling proteins (more on this in Section 2.6 below). This compact assembly involving a continuum of interactions throughout the extracellular and membrane-embedded domains is also consistent with proposals that structural rearrangements could mediate signal transduction through force-sensing [ 2 , 44 , 45 , 46 , 57 , 58 ], but a clear structural pathway from pMHC binding to initial phosphorylation events has yet to be identified [ 27 ].…”

“…Indeed, measurements of two-dimensional binding kinetics on intact T cells yield significantly higher affinities (due to slower off-rates) [ 42 , 43 ] and indicate that force [ 44 , 45 ] and even force directionality [ 46 ] play key roles in the unique binding characteristics governing TCR-pMHC interactions and their translation into activating signals. Although it is still unclear precisely how pMHC binding is transmitted across the T cell membrane [ 27 ], the complexity of the full TCR structure must be considered to begin to build an understanding.…”

“…This binding facilitates the sequestration of ITAM tyrosine residues into the lipid bilayer in their non-phosphorylated state [ 57 ], providing a layer of regulated accessibility to active Lck kinase that has been compared to the safety on the trigger of a gun [ 74 ]. Release of tail binding by, for example, force-induced structural changes that propagate through the TM domains of ligand-bound TCRs could thus provide a structural mechanism for initial receptor activation [ 2 , 27 , 57 , 58 , 75 ]. Signaling is amplified in part by the initial spike in intracellular free calcium (Ca ++ ), which competes with anionic lipids for tail binding and further propagates ITAM release and phosphorylation [ 76 ].…”

“…We begin to explore these questions by outlining the key features of natural immune receptors that relate to CAR design. For a more comprehensive treatment of the extensive literature relating to the structure and function of each receptor or protein family discussed below, we refer readers to recent reviews that are cited at appropriate places in the following sections and are also collected here [ 3 , 4 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 ] for convenience.…”

Cellular metabolism dictates T cell effector function in health and disease

“…ZAP70 initiates a signalling cascade that activates several signalling pathways including phospholipase Cγ1 (PLCγ1) that promotes calcium mobilization and activation of protein kinase C (PKC) and the RAS pathway. 14,15 The combination of these signalling cascades promotes activation of several transcription factors, including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), nuclear factor of activated T cells (NFAT) and activator protein 1 (AP-1). [16][17][18][19][20] Together, this induces the production and secretion of T cell-specific paracrine and autocrine growth factor IL-2.…”