Defects at the Posttranscriptional Level Account for the Low TCRζ Chain Expression Detected in Gastric Cancer Independently of Caspase-3 Activity

Aguinaga-Barrilero, Ana; Castro-Sánchez, Patricia; Juárez, Ignacio; Gutiérrez‐Calvo, Alberto; Rodríguez-Pérez, Noelia; López, Adela; Gómez, Remedios; Martin-Villa, José Manuel

doi:10.1155/2020/1039458

Cited by 2 publications

(2 citation statements)

References 35 publications

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“…Although several mechanisms may contribute to decrease  expression in tumour infiltrating T cells (12)(13)(14)(15)(16) the restoration of sufficient CD3 expression levels provides an attractive target for cancer immunotherapy. While CD3 determines TCR expression levels in primary human T cells, our experiments in HEK293T cells have shown that TCR surface expression can be achieved in the absence of .…”

Section: Discussionmentioning

confidence: 99%

Exploitation of CD3ζ to enhance TCR expression levels and antigen-specific T cell function

Degirmencay,

Thomas,

Holler

et al. 2024

Preprint

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The expression levels of TCRs on the surface of human T cells define the avidity of TCR-HLA/peptide interactions. In this study, we have explored which components of the TCR-CD3 complex are involved in determining the surface expression levels of TCRs in primary human T cells. The results show that there is a surplus of endogenous TCR α/β chains that can be mobilised by providing T cells with additional CD3γ,δ,ε,ζ chains, which leads to a 5-fold increase in TCR α/β surface expression. The analysis of individual CD3 chains revealed that provision of additional ζ chain alone was sufficient to achieve a 3-fold increase in endogenous TCR expression. Similarly, CD3ζ also limits the expression levels of exogenous TCRs transduced into primary human T cells. Interestingly, transduction with TCR plus CD3ζ not only increased surface expression of the introduced TCR, but it also reduced mispairing with endogenous TCR chains, resulting in improved antigen-specific function. TCR reconstitution experiments in HEK293 cells that do not express endogenous TCR or CD3 showed that TCRα/β and all four CD3 chains were required for optimal surface expression, while in the absence of CD3ζ the TCR expression was reduced by 50%. Together, the data show that CD3ζ is a key regulator of TCR expression levels in human T cells, and that gene transfer of exogenous TCR plus CD3ζ improved TCR surface expression, reduced TCR mispairing and increased antigen-specific function.

show abstract

Section: Discussionmentioning

confidence: 99%

Exploitation of CD3ζ to enhance TCR expression levels and antigen-specific T cell function

Degirmencay,

Thomas,

Holler

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…A critical role of CD3ζ in TCR expression and T cell function is supported by the observation that decreased ζ expression, associated with reduced TCR expression and impaired T cell function, has been described in tumour infiltrating T cells in various human cancers ( 9 ). Although several mechanisms may contribute to decrease ζ expression in tumour infiltrating T cells ( 10 – 14 ) the restoration of sufficient CD3ζ expression levels provides an attractive target for cancer immunotherapy.…”

Section: Discussionmentioning

confidence: 99%

Exploitation of CD3ζ to enhance TCR expression levels and antigen-specific T cell function

Degirmencay,

Thomas,

Holler

et al. 2024

Front. Immunol.

View full text Add to dashboard Cite

The expression levels of TCRs on the surface of human T cells define the avidity of TCR-HLA/peptide interactions. In this study, we have explored which components of the TCR-CD3 complex are involved in determining the surface expression levels of TCRs in primary human T cells. The results show that there is a surplus of endogenous TCR α/β chains that can be mobilised by providing T cells with additional CD3γ,δ,ε,ζ chains, which leads to a 5-fold increase in TCR α/β surface expression. The analysis of individual CD3 chains revealed that provision of additional ζ chain alone was sufficient to achieve a 3-fold increase in endogenous TCR expression. Similarly, CD3ζ also limits the expression levels of exogenous TCRs transduced into primary human T cells. Interestingly, transduction with TCR plus CD3ζ not only increased surface expression of the introduced TCR, but it also reduced mispairing with endogenous TCR chains, resulting in improved antigen-specific function. TCR reconstitution experiments in HEK293T cells that do not express endogenous TCR or CD3 showed that TCRα/β and all four CD3 chains were required for optimal surface expression, while in the absence of CD3ζ the TCR expression was reduced by 50%. Together, the data show that CD3ζ is a key regulator of TCR expression levels in human T cells, and that gene transfer of exogenous TCR plus CD3ζ improved TCR surface expression, reduced TCR mispairing and increased antigen-specific function.

show abstract

Defects at the Posttranscriptional Level Account for the Low TCRζ Chain Expression Detected in Gastric Cancer Independently of Caspase-3 Activity

Cited by 2 publications

References 35 publications

Exploitation of CD3ζ to enhance TCR expression levels and antigen-specific T cell function

Exploitation of CD3ζ to enhance TCR expression levels and antigen-specific T cell function

Exploitation of CD3ζ to enhance TCR expression levels and antigen-specific T cell function

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