Abstract
Doc number: 3
Abstract
Background: The T cell antigen receptors (TCR) of [alpha][beta] and [gamma][delta] T lymphocytes are believed to assemble in a similar fashion in humans. Firstly, [alpha][beta] or [gamma][delta] TCR chains incorporate a CD3[delta][straight epsilon] dimer, then a CD3[gamma][straight epsilon] dimer and finally a ζζ homodimer, resulting in TCR complexes with the same CD3 dimer stoichiometry. Partial reduction in the expression of the highly homologous CD3[gamma] and CD3[delta] proteins would thus be expected to have a similar impact in the assembly and surface expression of both TCR isotypes. To test this hypothesis, we compared the surface TCR expression of primary [alpha][beta] and [gamma][delta] T cells from healthy donors carrying a single null or leaky mutation in CD3G ([gamma]+/- ) or CD3D ([delta]+/- , [delta]+/leaky ) with that of normal controls.
Results: Although the partial reduction in the intracellular availability of CD3[gamma] or CD3[delta] proteins was comparable as a consequence of the mutations, surface TCR expression measured with anti-CD3[straight epsilon] antibodies was significantly more decreased in [gamma][delta] than in [alpha][beta] T lymphocytes in CD3[gamma]+/- individuals, whereas CD3[delta]+/- and CD3[delta]+/leaky donors showed a similar decrease of surface TCR in both T cell lineages. Therefore, surface [gamma][delta] TCR expression was more dependent on available CD3[gamma] than surface [alpha][beta] TCR expression.
Conclusions: The results support the existence of differential structural constraints in the two human TCR isotypes regarding the incorporation of CD3[gamma][straight epsilon] and CD3[delta][straight epsilon] dimers, as revealed by their discordant surface expression behaviour when confronted with reduced amounts of CD3[gamma], but not of the homologous CD3[delta] chain. A modified version of the prevailing TCR assembly model is proposed to accommodate these new data.
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