Editors' ChoiceImmunology

The basics of mechanotransduction

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Sci. Signal.  13 Nov 2018:
Vol. 11, Issue 556, eaau2223
DOI: 10.1126/scisignal.aau2223

Basic residues in the transmembrane domain of the T cell receptor α chain promote its association with CD3 signaling chains.

Required for T cell function, the T cell receptor (TCR) is a complex of the TCRα and TCRβ antigen recognition chains with CD3εγ, CD3εδ, and CD3ζζ dimeric signaling chains. Heterodimerization of TCRαβ, CD3εγ, and CD3εδ depends on interactions between extracellular domains, whereas interchain disulfide bonds promote CD3ζζ homodimerization. However, precisely how the CD3 signaling chains associate with TCRαβ remains unclear. Using nuclear magnetic resonance (NMR) spectroscopy of phospholipid micelles, Brazin et al. found that the TCRα transmembrane domain and cytoplasmic tail formed an L-shaped structure composed of two α-helices connected by a highly dynamic hinge. The authors showed that within the transmembrane helix of TCRα, the conserved basic residue Lys256 promoted shallow TCRα insertion into the plasma membrane and association with cell surface CD3 signaling chains, which was necessary for TCR-stimulated Ca2+ flux and production of the cytokine interleukin-2 (IL-2). The association of TCRα with CD3δ also required previously identified motifs within TCRα and CD3δ. All TCRα mutants that reduced their association with the CD3 signaling chains reduced T cell activation as determined by measurement of IL-2 production and single-cell force measurements using optical tweezers. In contrast, mutation of another basic residue in the TCRα transmembrane region important for the association with CD3ζζ but not CD3εγ, R251L, reduced the force required to stimulate Ca2+ flux. These data reveal that CD3 signaling chains associate with specific basic residues within the TCRα transmembrane domain and suggest that CD3ζζ dissociation from the TCR complex may promote T cell activation. Because dissociation of CD3 signaling chains occurs after TCR activation and is observed in nonfunctional tumor–infiltrating T cells, understanding how CD3 signaling chains associate with TCRα may help guide the design of TCR-based therapies that resist inactivation.

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