Human CD3γ, but not CD3δ, haploinsufficiency differentially impairs γδ versus αβ surface TCR expression
Open Access
- 21 January 2013
- journal article
- research article
- Published by Springer Science and Business Media LLC in BMC Immunology
- Vol. 14 (1), 3
- https://doi.org/10.1186/1471-2172-14-3
Abstract
Background: The T cell antigen receptors (TCR) of αβ and γδ T lymphocytes are believed to assemble in a similar fashion in humans. Firstly, αβ or γδ TCR chains incorporate a CD3δε dimer, then a CD3γε 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 CD3γ and CD3δ 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 αβ and γδ T cells from healthy donors carrying a single null or leaky mutation inCD3G(γ+/−) orCD3D(δ+/−, δ+/leaky) with that of normal controls.Results: Although the partial reduction in the intracellular availability of CD3γ or CD3δ proteins was comparable as a consequence of the mutations, surface TCR expression measured with anti-CD3ε antibodies was significantly more decreased in γδ than in αβ T lymphocytes in CD3γ+/−individuals, whereas CD3δ+/−and CD3δ+/leakydonors showed a similar decrease of surface TCR in both T cell lineages. Therefore, surface γδ TCR expression was more dependent on available CD3γ than surface αβ TCR expression.Conclusions: The results support the existence of differential structural constraints in the two human TCR isotypes regarding the incorporation of CD3γε and CD3δε dimers, as revealed by their discordant surface expression behaviour when confronted with reduced amounts of CD3γ, but not of the homologous CD3δ chain. A modified version of the prevailing TCR assembly model is proposed to accommodate these new data.Keywords
This publication has 19 references indexed in Scilit:
- A leaky mutation in CD3D differentially affects αβ and γδ T cells and leads to a Tαβ–Tγδ+B+NK+ human SCIDJCI Insight, 2011
- Distinctive CD3 Heterodimeric Ectodomain Topologies Maximize Antigen-Triggered Activation of αβ T Cell ReceptorsThe Journal of Immunology, 2010
- Structural Biology of the T-cell Receptor: Insights into Receptor Assembly, Ligand Recognition, and Initiation of SignalingCold Spring Harbor Perspectives in Biology, 2010
- Different composition of the human and the mouse γδ T cell receptor explains different phenotypes of CD3γ and CD3δ immunodeficienciesThe Journal of Experimental Medicine, 2007
- The Impact of Single Amino Acid Substitutions in CD3γ on the CD3ϵγ Interaction and T-Cell Receptor–CD3 Complex FormationHuman Immunology, 2006
- Severe combined immunodeficiency caused by a splicing abnormality of the CD3? geneEuropean Journal of Pediatrics, 2005
- Human γδ T Cells Express a Higher TCR/CD3 Complex Density Than αβ T CellsClinical Immunology, 2001
- Phenotypical and functional characterization of Herpesvirus saimiri‐immortalized human major histocompatibility complex class ll‐deficient T lymphocytesTissue Antigens, 1998
- Immunophenotyping of blood lymphocytes in childhoodReference values for lymphocyte subpopulationsThe Journal of Pediatrics, 1997
- An in Vivo Functional Immune System Lacking Polyclonal T‐Cell Surface Expression of the CD3/Ti(WT31) ComplexScandinavian Journal of Immunology, 1987