Reciprocal TCR-CD3 and CD4 Engagement of a Nucleating pMHCII Stabilizes a Functional Receptor Macrocomplex
AffiliationUniv Arizona, Coll Med, Dept Immunobiol
Univ Arizona, Coll Med
Univ Arizona, Coll Med, Arizona Ctr Aging
Univ Arizona, Coll Med, Canc Ctr
MetadataShow full item record
CitationReciprocal TCR-CD3 and CD4 Engagement of a Nucleating pMHCII Stabilizes a Functional Receptor Macrocomplex 2018, 22 (5):1263 Cell Reports
Rights© 2017 The Author(s). This is an open access article under the CC BY-NC-ND license.
Collection InformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at firstname.lastname@example.org.
AbstractCD4(+) T cells convert the time that T cell receptors (TCRs) interact with peptides embedded within class II major histocompatibility complex molecules (pMHCII) into signals that direct cell-fate decisions. In principle, TCRs relay information to intracellular signaling motifs of the associated CD3 subunits, while CD4 recruits the kinase Lck to those motifs upon coincident detection of pMHCII. But the mechanics by which this occurs remain enigmatic. In one model, the TCR and CD4 bind pMHCII independently, while in another, CD4 interacts with a composite surface formed by the TCR-CD3 complex bound to pMHCII. Here, we report that the duration of TCR-pMHCII interactions impact CD4 binding to MHCII. In turn, CD4 increases TCR confinement to pMHCII via reciprocal interactions involving membrane distal and proximal CD4 ectodomains. The data suggest that a precisely assembled macrocomplex functions to reliably convert TCR-pMHCII confinement into reproducible signals that orchestrate adaptive immunity.
NoteUA Open Access Publishing Fund.
VersionFinal published version
SponsorsCancer Center Support Grant [CCSG-CA 023074]; Pew Charitable Trusts; University of Arizona College of Medicine; Bio5 Institute; NIH/NIAID [R01AI101053]
- The CD4 and CD3δε Cytosolic Juxtamembrane Regions Are Proximal within a Compact TCR-CD3-pMHC-CD4 Macrocomplex.
- Authors: Glassman CR, Parrish HL, Deshpande NR, Kuhns MS
- Issue date: 2016 Jun 1
- Functional evidence for TCR-intrinsic specificity for MHCII.
- Authors: Parrish HL, Deshpande NR, Vasic J, Kuhns MS
- Issue date: 2016 Mar 15
- Crystal structure of the human CD4 N-terminal two-domain fragment complexed to a class II MHC molecule.
- Authors: Wang JH, Meijers R, Xiong Y, Liu JH, Sakihama T, Zhang R, Joachimiak A, Reinherz EL
- Issue date: 2001 Sep 11
- T Cell Receptor Binding to a pMHCII Ligand Is Kinetically Distinct from and Independent of CD4.
- Authors: Xiong Y, Kern P, Chang H, Reinherz E
- Issue date: 2001 Feb 23
- Energetic and flexibility properties captured by long molecular dynamics simulations of a membrane-embedded pMHCII-TCR complex.
- Authors: Bello M, Correa-Basurto J
- Issue date: 2016 Apr