Design of TCR Structural Variants That Retain or Invert the Normal Activation Signal.

Jee-Young Mock, Julyun Oh, Jason Yi, Mark E Daris, Agnes Hamburger, Alexander Kamb

ImmunoHorizons 2021 May 26

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We designed variant human TCRs composed of the full-length TCRα/β or extracellular and transmembrane domains of the associated CD3 subunits fused to polypeptides derived from proteins thought to either enhance or inhibit normal T cell function. First, we showed that the C termini of both the TCR α- and β-chains can accommodate specific additional sequences, without abrogating complex formation or acute sensitivity of the receptor. Replacement of ITAMs with ITIM-containing intracellular domains inverted the TCR signal (i.e., created a ligand-dependent inhibitory receptor). The normal signaling function of the CD3 complex was transferable to the TCR by eliminating all CD3 ITAMs and grafting three to six ITAMs onto the C termini of the α/β-chains, with no effect on acute sensitivity. The observation that TCR variants of such diverse C-terminal composition can fold and function as signaling receptors demonstrates substantial structural and functional malleability of TCRs. These results add to knowledge about TCR structure-function with regard to acute signaling and may provide a route to use TCRs in different ways for T cell therapy. Copyright © 2021 The Authors.

Citation

Jee-Young Mock, Julyun Oh, Jason Yi, Mark E Daris, Agnes Hamburger, Alexander Kamb. Design of TCR Structural Variants That Retain or Invert the Normal Activation Signal. ImmunoHorizons. 2021 May 26;5(5):349-359