Research ArticleImmunology

Cooperativity Between T Cell Receptor Complexes Revealed by Conformational Mutants of CD3ɛ

Sci. Signal.  11 Aug 2009:
Vol. 2, Issue 83, pp. ra43
DOI: 10.1126/scisignal.2000402

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Must Change Shape

The T cell antigen receptor (TCR) complex consists of the TCR αβ subunits noncovalently associated with the δ, ɛ, γ, and ζ subunits of CD3. Engagement of the TCR by peptide bound to the major histocompatibility complex (MHC) on the surface of an antigen-presenting cell triggers the phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) in the CD3 subunits, and these motifs recruit the proteins that mediate TCR signaling. With a molecular dynamics model, Martínez-Martín et al. investigated how extracellular binding of antigen to the TCR is transduced to the inside of the cell. They identified two residues in CD3ɛ that were critical for the transmission of ligand-induced conformational changes to the intracellular portions of this subunit. CD3ɛ subunits with mutations in either of these residues blocked transmission of the conformational change, and one of these variants functioned as a dominant-negative inhibitor of TCR signaling and T cell activation even when present at very low abundance. The authors propose that the initial interaction of an antigen with a TCR may influence the conformation of oligomeric TCR complexes so that TCRs act cooperatively to transmit signals from peptide-MHC.