Expression of fully assembled TCR-CD3 complex on double positive thymocytes: synergistic role for the PRS and ER retention motifs in the intra-cytoplasmic tail of CD3

Brodeur, Jean-Francois; Li, Samantha; Damlaj, Ousama; Davé, Vibhuti P.

doi:10.1093/intimm/dxp098

Cited by 12 publications

(8 citation statements)

References 49 publications

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“…Therefore, some basal open-CD3 occurs in the absence of TCR:pMHC engagement by conventional MHC-based ligands. Basal open-CD3 could sustain the ligand-independent regulation of TCR–CD3 surface expression level in DP thymocytes proposed in previous reports (12, 13, 16). In addition, different thymocyte subsets may possibly exhibit distinct levels of open-CD3 that could contribute to the basal levels we measure from the bulk thymocyte population.…”

Section: Discussionsupporting

confidence: 66%

“…PRS deficiency was shown to correlate with increased TCR–CD3 expression, implying that the PRS controls constitutive expression of the receptor in double-positive (DP) thymocytes. Independent work has since corroborated the role of the CD3ε PRS in regulating TCR–CD3 ubiquitylation and expression in DP thymocytes while additionally demonstrating PRS activity in promoting proliferation of double-negative thymocytes (13–16). Considering all studies together, it is currently not clear whether the initial interpretation that CD3Δc is required to induce PRS accessibility is correct, whether thymocytes are unique by expressing the PRS in a constitutively accessible conformation, or whether differences in experimental systems account for the discrepant observations (17).…”

mentioning

confidence: 94%

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Basal and Antigen-Induced Exposure of the Proline-Rich Sequence in CD3ε

Cruz

Kruger

Parks

et al. 2011

The Journal of Immunology

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The CD3ε cytoplasmic tail contains a conserved proline-rich sequence (PRS) that influences TCR–CD3 expression and signaling. Although the PRS can bind the SH3.1 domain of the cytosolic adapter Nck, whether the PRS is constitutively available for Nck binding or instead represents a cryptic motif that is exposed via conformational change upon TCR–CD3 engagement (CD3Δc) is currently unresolved. Furthermore, the extent to which a cis-acting CD3ε basic amino acid-rich stretch (BRS), with its unique phosphoinositide-binding capability, might impact PRS accessibility is not clear. In this study, we found that freshly harvested primary thymocytes expressed low to moderate basal levels of Nck-accessible PRS (“open-CD3”), although most TCR–CD3 complexes were inaccessible to Nck (“closed-CD3”). Ag presentation in vivo induced open-CD3, accounting for half of the basal level found in thymocytes from MHC+ mice. Additional stimulation with either anti-CD3 Abs or peptide–MHC ligands further elevated open-CD3 above basal levels, consistent with a model wherein antigenic engagement induces maximum PRS exposure. We also found that the open-CD3 conformation induced by APCs outlasted the time of ligand occupancy, marking receptors that had been engaged. Finally, CD3ε BRS–phosphoinositide interactions played no role in either adoption of the initial closed-CD3 conformation or induction of open-CD3 by Ab stimulation. Thus, a basal level of open-CD3 is succeeded by a higher, induced level upon TCR–CD3 engagement, involving CD3Δc and prolonged accessibility of the CD3ε PRS to Nck.

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Section: Discussionsupporting

confidence: 66%

mentioning

confidence: 94%

Basal and Antigen-Induced Exposure of the Proline-Rich Sequence in CD3ε

Cruz

Kruger

Parks

et al. 2011

The Journal of Immunology

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“…The Nck adapters have been implicated in the regulation of the surface levels of the TCR (11,22,23). The levels of TCR expression are finely regulated at the DP stage (24), as both positive and negative selection depend on the strength of TCR signaling (25).…”

Section: Nck Deletion Results In Tcr Overexpression On Dp Thymocytesmentioning

confidence: 99%

Fine Tuning of the Threshold of T Cell Selection by the Nck Adapters

Roy

Togbé

Holdorf

et al. 2010

The Journal of Immunology

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Thymic selection shapes the T cell repertoire to ensure maximal antigenic coverage against pathogens while preventing autoimmunity. Recognition of self-peptides in the context of peptide-MHC complexes by the TCR is central to this process, which remains partially understood at the molecular level. In this study we provide genetic evidence that the Nck adapter proteins are essential for thymic selection. In vivo Nck deletion resulted in a reduction of the thymic cellularity, defective positive selection of low-avidity T cells, and impaired deletion of thymocytes engaged by low-potency stimuli. Nck-deficient thymocytes were characterized by reduced ERK activation, particularly pronounced in mature single positive thymocytes. Taken together, our findings identify a crucial role for the Nck adapters in enhancing TCR signal strength, thereby fine-tuning the threshold of thymocyte selection and shaping the preimmune T cell repertoire.

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“…Apart from critically influencing pre‐TCR function, the CD3ε cytoplasmic motifs were found to affect TCR expression on DP thymocytes as well. It was observed that mutation of the PRS and ER retention motifs of CD3ε increased TCR expression on DP thymocytes in a cooperative fashion (79, 80).…”

Section: Cd3 Chains In Thymocyte Developmentmentioning

confidence: 99%

Hierarchical role of CD3 chains in thymocyte development

Davé

2009

Immunological Reviews

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Assembly, expression, and signal transduction by the pre-T-cell receptor (pre-TCR) and TCR complexes are critical for normal thymocyte development. How environmental cues sensed by these two receptor complexes are translated into biological responses that result in the generation of functionally mature T cells is increasingly better understood. Invariant CD3gamma, delta, epsilon, and zeta polypeptides are central to the function of these two receptor complexes. CD3 chains ensure correct intracellular assembly, surface expression, and signal transduction via the receptors in ligand-independent and -dependent manners. In the present review, the roles of the CD3 chains, particularly CD3gamma, delta, and epsilon, in thymocyte differentiation in mice and humans are reviewed.

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Expression of fully assembled TCR-CD3 complex on double positive thymocytes: synergistic role for the PRS and ER retention motifs in the intra-cytoplasmic tail of CD3

Cited by 12 publications

References 49 publications

Basal and Antigen-Induced Exposure of the Proline-Rich Sequence in CD3ε

Basal and Antigen-Induced Exposure of the Proline-Rich Sequence in CD3ε

Fine Tuning of the Threshold of T Cell Selection by the Nck Adapters

Hierarchical role of CD3 chains in thymocyte development

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