Coreceptors and TCR Signaling – the Strong and the Weak of It

Abstract

The T-cell coreceptors CD4 and CD8 have well-characterized and essential roles in thymic development, but how they contribute to immune responses in the periphery is unclear. Coreceptors strengthen T-cell responses by many orders of magnitudebeyond a million-fold according to some estimates-but the mechanisms underlying these effects are still debated. T-cell receptor (TCR) triggering is initiated by the binding of the TCR to peptide-loaded major histocompatibility complex (pMHC) molecules on the surfaces of other cells. CD4 and CD8 are the only T-cell proteins that bind to the same pMHC ligand as the TCR, and can directly associate with the TCRphosphorylating kinase Lck. At least three mechanisms have been proposed to explain how coreceptors so profoundly amplify TCR signaling: (1) the Lck recruitment model and (2) the pseudodimer model, both invoked to explain receptor triggering per se, and (3) two-step coreceptor recruitment to partially triggered TCRs leading to signal amplification. More recently it has been suggested that, in addition to initiating or augmenting TCR signaling, coreceptors effect antigen discrimination. But how can any of this be reconciled with TCR signaling occurring in the absence of CD4 or CD8, and with their interactions with pMHC being among the weakest specific protein-protein interactions ever described? Here, we review each theory of coreceptor function in light of the latest structural, biochemical, and functional data. We conclude that the oldest ideas are probably still the best, i.e., that their weak binding to MHC proteins and efficient association with Lck allow coreceptors to amplify weak incipient triggering of the TCR, without comprising TCR specificity.

How the biomimetic assembly of membrane receptors into multivalent domains is regulated by a small ligand

“…30 Our mathematical model may nonetheless nd application in the study of cell adhesion phenomena that rely on assembly of many copies of relatively weakly binding ligands and receptors. 31,32…”

Cancer Therapy With TCR-Engineered T Cells: Current Strategies, Challenges, and Prospects

“…In humans, antigen-presenting MHC alleles are broadly classified as HLA class I (A, B, or C) or HLA class II (DR, DP, or DQ), which predominantly present cytosolic or extracellular derived peptides, respectively ( 4 ). The coreceptors CD8 and CD4 enhance TCR antigen sensitivity through interaction with MHC class I or II molecules, respectively ( 8 ). TCR binding to cognate pMHC leads to the phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) in intracellular regions of the CD3 subunits ( 5 , 6 ), which results in T cell activation and initiation of effector functions including proliferation, cytokine secretion, and cytolysis via secretion of perforin and granzyme ( Figure 1 ).…”

T Cell Memory in Infection, Cancer, and Autoimmunity

“…The resolution of most acute infections or the vaccination against the related pathogens (e.g., smallpox, mumps, rubella, chickenpox, measles, diphtheria, polio, meningococci, hepatitis A virus [HAV], HBV) correlate with protective adaptive effector responses (i.e., neutralizing antibodies and effector CD4 + and CD8 + T cells) and development of long-term memory (Figures 2A, B). In particular, high affinity TCRs and the coreceptors (CD4 or CD8) on naïve T cells, following receiving sustained antigenic signals 1 by pAPCs, deliver the signaling cascades through the phosphorylation of multiple consecutive molecules (e.g., ITAM, ZAP70, LCK, LAT, PLCg, IP3,…), ultimately leading to the nucleus translocation of various transcription factors (TFs) (e.g., NFkB, NAFT family) that, through their own conserved DNA binding domains, favor the expression of a wide series of genes associated to T cell activation and memory (25)(26)(27)(28). The costimulatory molecules on naïve T cells (engaged by the respective ligands expressed on APCs [signal 2]) amplify the activation signal cascade, through the phosphorylation of additional messengers (e.g., PIK3, ERK, RAS…) essential for T cell priming, without which signal 1 alone could cause T cell anergy.…”