The Transmembrane Adaptor Protein Trim Regulates T Cell Receptor (Tcr) Expression and Tcr-Mediated Signaling via an Association with the Tcr ζ Chain

Kirchgessner, h.c. mult. M.; Dietrich, Jes; Scherer, Jeanette; Isomäki, Pia; Kor̆ínek, Vladimír; Hilgert, I; Bruyns, Eddy; Leo, Albrecht; Cope, Andrew P.; Schraven, Burkhart

doi:10.1084/jem.193.11.1269

Cited by 58 publications

(81 citation statements)

References 37 publications

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“…Ahmed and coworkers (2) recently showed that the IL-7 receptor is selectively expressed in MEM T cells. The T cell receptor-interacting molecule is a recently identified transmembrane adaptor protein that is exclusively expressed in mature T cells (15). EFFE up, MEM intermediary, NAI down.…”

Section: Resultsmentioning

confidence: 99%

Memory T cells have gene expression patterns intermediate between naïve and effector

Holmes

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Section: Resultsmentioning

confidence: 99%

Memory T cells have gene expression patterns intermediate between naïve and effector

Holmes

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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“…Although it is not fully understood how TCR surface expression levels are regulated, it seems to involve protein kinases (2,9,10,19), phosphorylation status of the TCR chains (9,19), and adaptor proteins such as TCR-interacting molecule (35,36) and src-like adaptor protein (30). The present study was performed to broaden our knowledge of the mechanisms regulating constitutive TCR cycling and ligand-induced TCR internalization.…”

Section: Discussionmentioning

confidence: 99%

Ligand-Induced TCR Down-Regulation Is Not Dependent on Constitutive TCR Cycling

Dietrich

Menné

Lauritsen

et al. 2002

The Journal of Immunology

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TCR internalization takes place both in resting T cells as part of constitutive TCR cycling, after PKC activation, and during TCR triggering. It is still a matter of debate whether these pathways represent distinct pathways. Thus, some studies have indicated that ligand-induced TCR internalization is regulated by mechanisms distinct from those involved in constitutive internalization, whereas other studies have suggested that the ligand-induced TCR internalization pathway is identical with the constitutive pathway. To resolve this question, we first identified requirements for constitutive TCR cycling. We found that in contrast to PKC-induced TCR internalization where both CD3γ-S126 and the CD3γ leucine-based internalization motif are required, constitutive TCR cycling required neither PKC nor CD3γ-S126 but only the CD3γ leucine-based motif. Having identified these requirements, we next studied ligand-induced internalization in cells with abolished constitutive TCR cycling. We found that ligand-induced TCR internalization was not dependent on constitutive TCR internalization. Likewise, constitutive internalization and recycling of the TCR were independent of an intact ligand-induced internalization of the TCR. In conclusion, ligand-induced TCR internalization and constitutive cycling of the TCR represents two independent pathways regulated by different mechanisms.

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“…3), making the TCR␣␤: strategy more universal with respect to TCR-V regions. In addition, the enhanced surface expression and function of TCR␣␤: may be linked to TCR-interacting molecule, an adaptor molecule that normally associates with CD3 and contributes to TCR expression and signaling (48). Also, the absence of glycosylation sites that are normally present in TCR-C␣ and ␤ (a total of four sites in human TCR␣␤) may result in enhanced expression and avidity of TCR␣␤: (55).…”

Section: Discussionmentioning

confidence: 99%

Human TCR That Incorporate CD3ζ Induce Highly Preferred Pairing between TCRα and β Chains following Gene Transfer

Sebestyén¹,

Schooten²,

Sals³

et al. 2008

The Journal of Immunology

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TCR gene therapy is adversely affected by newly formed TCRαβ heterodimers comprising exogenous and endogenous TCR chains that dilute expression of transgenic TCRαβ dimers and are potentially self-reactive. We have addressed TCR mispairing by using a modified two-chain TCR that encompasses total human CD3ζ with specificities for three different Ags. Transfer of either TCRα:CD3ζ or β:CD3ζ genes alone does not result in surface expression, whereas transfer of both modified TCR chains results in high surface expression, binding of peptide-MHC complexes and Ag-specific T cell functions. Genetic introduction of TCRαβ:ζ does not compromise surface expression and functions of an endogenous TCRαβ. Flow cytometry fluorescence resonance energy transfer and biochemical analyses demonstrate that TCRαβ:CD3ζ is the first strategy that results in highly preferred pairing between CD3ζ-modified TCRα and β chains as well as absence of TCR mispairing between TCR:CD3ζ and nonmodified TCR chains. Intracellular assembly and surface expression of TCR:CD3ζ chains is independent of endogenous CD3γ, δ, and ε. Taken together, our data support the use of TCRαβ:CD3ζ to prevent TCR mispairing, which may provide an adequate strategy to enhance efficacy and safety of TCR gene transfer.

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The Transmembrane Adaptor Protein Trim Regulates T Cell Receptor (Tcr) Expression and Tcr-Mediated Signaling via an Association with the Tcr ζ Chain

Cited by 58 publications

References 37 publications

Memory T cells have gene expression patterns intermediate between naïve and effector

Memory T cells have gene expression patterns intermediate between naïve and effector

Ligand-Induced TCR Down-Regulation Is Not Dependent on Constitutive TCR Cycling

Human TCR That Incorporate CD3ζ Induce Highly Preferred Pairing between TCRα and β Chains following Gene Transfer

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