Human CD3γ, but not CD3δ, haploinsufficiency differentially impairs γδ versus αβ surface TCR expression

Abstract

BackgroundThe 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 in CD3G (γ+/−) or CD3D (δ+/−, δ+/leaky) with that of normal controls.ResultsAlthough 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+/leaky donors 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.ConclusionsThe 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.

Acquired Senescent T-Cell Phenotype Correlates with Clinical Severity in GATA Binding Protein 2-Deficient Patients

“…In this study, three patients out of four had increased frequencies of TCRγδ T cells and all had expanded NKT-cell populations. An elevation of TCRγδ T cells has been observed in some combined immunodeficiencies such as recombination activating gene 1,2 deficiency ( 21 , 22 ), CD3γ, and CD3δ ( 23 , 24 ), as a consequence of CMV infection or delayed-onset combined immune deficiency with granuloma and/or autoimmunity ( 25 – 27 ). While the source of the defect in innate-like T cells in GATA2 deficiency is unclear, it is possible that the markedly reduced numbers of antigen presenting cells (DC, monocytes, and B cells) could produce a dysregulated increase of invariant T cells such as TCRγδ and NKT cells ( 9 ).…”

γδ T Lymphocytes in the Diagnosis of Human T Cell Receptor Immunodeficiencies

“…When surface TCR expression is low, αβ T cells can be identified by the expression of CD4 or CD8αβ (i.e., CD8 bright ) within the lymphoid subset ( 23 ), whereas γδ T cells are identified only by expression of the γδTCR. We have reported that most CD3 + cells within normal DN lymphocytes are γδ T cells ( 34 ), and this may also help in certain TCRID.…”

Identifying and analyzing different cancer subtypes using RNA-seq data of blood platelets

“…ENSG00000160654, CD3G, has also been extracted as a candidate biomarker. CD3G has been widely reported to participate in antigen recognition associated biological processes, coupling antigen recognition to specific intracellular signal transduction pathways [ 101 , 102 ]. Encoding a specific protein that can be easily detected by liquid biopsy, CD3G has been confirmed to be differentially expressed, and may be a direct target of different functional microRNA targets different subtypes [ 103 ].…”