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textabstractTCR gene therapy represents a feasible and promising treatment for patients with cancer and virus infections. Currently, this treatment rationale is hampered by diluted surface expression of the TCR transgene and generation of potentially self reactive T-cells, both a direct consequence of mis-pairing with endogenous TCR chains. As we reported previously (Gene Ther 16:1369, 2000; J Immunol 180:7736, 2008), TCR mis-pairing can be successfully addressed by a TCR:CD3ζ fusion protein (i.e., TCR:ζ). Here, we set out to minimize the content of CD3ζ in TCR:ζ, specific for MAGEA1/ HLA-A1, without compromising TCR pairing and function. Domain-exchange and 3D-modeling strategies defined a set of minimal TCR:ζ variants, which, together with a murinized and cysteine-modified TCR (TCR:mu+cys), were tested for functional TCR expression and TCR pairing. Our data with Jurkat T cells show that the CD3ζ transmembrane domain is important for cell-surface expression, whereas the CD3ζ intracellular domain is crucial for T-cell activation. Notably, inability of TCR:ζ to mis-pair was not observed for TCR:mu+cys, which depended exclusively on the transmembrane domain of CD3ζ and could not be recapitulated by a limited number of structurally defined CD3ζ transmembrane amino acids. The extracellular CD3ζ domain was dispensable for TCR:ζ's ability to prevent TCR mis-pairing, bind pMHC and mediate NFAT activation. In primary human T cells, however, minimal TCR:ζ without CD3ζ's extracellular domain but not TCR:ζ nor TCR:mu+cys revealed compromised cell surface expression and T cell function. Taken together, our study demonstrates that CD3ζ's transmembrane domain dictates TCR:ζ's inability to TCR mis-pair, but only TCR coupled to complete CD3ζ and not its minimal variants were functionally expressed in primary T cells

T Cell Receptor Fused to CD3ζ: Transmembrane Domain of CD3ζ Prevents TCR Mis-Pairing, Whereas Complete CD3ζ Directs Functional TCR Expression