Variability of invariant mouse CD3ε chains detected by anti-CD3 antibodies

Criado, Gabriel; Feito, María José; Ojeda, Gloria; Sánchez, Alejandra; Janeway, Charles A.; Portolés, Pilàr; Rojo, José María

doi:10.1002/(sici)1521-4141(200005)30:5<1469::aid-immu1469>3.0.co;2-v

Cited by 9 publications

(42 citation statements)

References 27 publications

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“…Notably, the same group reported that CD4 + Foxp3 + T cells isolated from C57BL/6 mice have more undegraded CD3ε and less N-terminal-degraded CD3ε isoforms than do CD4 + Foxp3 2 T cells. This feature accounts for the difference in the avidity to two anti-CD3 (namely, the YCD3-1 and 500A2 clones) (17,35). However, neither of the previously cited studies demonstrated either the ability of nonmitogenic tolerogenic anti-CD3 (i.e., the 145-2C11 clone used in our study) to discriminate the two different isoforms, or the expression of differing CD3ε isoforms in T cells from NOD mice (17,35).…”

Section: Discussioncontrasting

confidence: 57%

“…However, preliminary results seem to exclude that the recycling rate of CD3 molecules on the cell surface account for that (A. Valle, unpublished observation). Alternatively, Rojo and colleagues (35,36) demonstrated that two different isoforms of CD3ε are simultaneously present on murine CD4 + T cells. The said isoforms differ in the N-terminal chain length, which is alternatively degraded by extracellular proteases (35).…”

Section: Discussionmentioning

confidence: 99%

“…Alternatively, Rojo and colleagues (35,36) demonstrated that two different isoforms of CD3ε are simultaneously present on murine CD4 + T cells. The said isoforms differ in the N-terminal chain length, which is alternatively degraded by extracellular proteases (35). Cells expressing N-terminal-degraded CD3ε show enhanced response to TCR stimulation (36).…”

Section: Discussionmentioning

confidence: 99%

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Heterogeneous CD3 Expression Levels in Differing T Cell Subsets Correlate with the In Vivo Anti-CD3–Mediated T Cell Modulation

Valle

Barbagiovanni

Jofra³

et al. 2015

The Journal of Immunology

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The tolerogenic anti-CD3ε monoclonal Abs (anti-CD3) are promising compounds for the treatment of type 1 diabetes. Anti-CD3 administration induces transient T cell depletion both in preclinical and in clinical studies. Notably, the said depletion mainly affects CD4+ but not CD8+ T cells. Moreover, type 1 diabetes reversal in preclinical models is accompanied by the selective expansion of CD4+Foxp3+ T regulatory (Treg) cells, which are fundamental for the long-term maintenance of anti-CD3–mediated tolerance. The mechanisms that lead to this immune-shaping by affecting mainly CD4+ T effector cells while sparing CD4+Foxp3+ Treg cells have still to be fully elucidated. This study shows that CD3 expression levels differ from one T cell subset to another. CD4+Foxp3− T cells contain higher amounts of CD3 molecules than do CD4+Foxp3+ and CD8+ T cells in both mice and humans. The said differences correlate with the anti-CD3–mediated immune resetting that occurs in vivo after anti-CD3 administration in diabetic NOD mice. Additionally, transcriptome analysis demonstrates that CD4+Foxp3+ Treg cells are significantly less responsive than are CD4+Foxp3− T cells to anti-CD3 treatment at a molecular level. Thus, heterogeneity in CD3 expression seems to confer to the various T cell subsets differing susceptibility to the in vivo tolerogenic anti-CD3–mediated modulation. These data shed new light on the molecular mechanism that underlies anti-CD3–mediated immune resetting and thus may open new opportunities to improve this promising treatment.

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Section: Discussioncontrasting

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Heterogeneous CD3 Expression Levels in Differing T Cell Subsets Correlate with the In Vivo Anti-CD3–Mediated T Cell Modulation

Valle

Barbagiovanni

Jofra³

et al. 2015

The Journal of Immunology

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“…In a previous study (18), we detected differences in the recognition of mouse CD3 by monoclonal antibodies that were linked to differences in the N-terminal sequence of CD3⑀ as determined by recognition with an N-terminal peptide-specific antibody. These differences were not due to alternative splicing of the mini-exons coding for the N-terminal sequence of CD3⑀, but were due to degradation by proteinases (including metalloproteinases) sensitive to phenanthroline.…”

mentioning

confidence: 96%

“…These differences were not due to alternative splicing of the mini-exons coding for the N-terminal sequence of CD3⑀, but were due to degradation by proteinases (including metalloproteinases) sensitive to phenanthroline. Interestingly, the association of CD3 with the TCR is weaker when CD3⑀ N-terminal sequences are degraded (18). Here, we have taken advantage of the presence of negatively charged amino acid residues in the N-terminal sequence of CD3⑀ to further analyze this phenomenon.…”

mentioning

confidence: 99%

Loss of N-terminal Charged Residues of Mouse CD3ɛ Chains Generates Isoforms Modulating Antigen T Cell Receptor-mediated Signals and T Cell Receptor-CD3 Interactions

Bello

Feito

Ojeda

et al. 2007

Journal of Biological Chemistry

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The antigen T cell receptor (TCR)-CD3 complexes present on the cell surface of CD4؉ T lymphocytes and T cell lines express CD3⑀ chain isoforms with different isoelectric points (pI), with important structural and functional consequences. The pI values of the isoforms fit the predicted pI values of CD3⑀ chains lacking one, two, and three negatively charged amino acid residues present in the N-terminal region. Different T cells have different ratios of CD3⑀ chain isoforms. At a high pI, degraded CD3⑀ isoforms can be better recognized by certain anti-CD3 monoclonal antibodies such as YCD3-1, the ability of which to bind to the TCR-CD3 complex is directly correlated with the pI of CD3⑀. The abundance of CD3⑀ isoforms can be modified by treatment of T cells with the proteinase inhibitor phenanthroline. In addition, these CD3⑀ isoforms have functional importance. This is shown, first, by the different structure of TCR-CD3 complexes in cells possessing different amounts of isoforms (as observed in surface biotinylation experiments), by their different antigen responses, and by the stronger interaction between low pI CD3⑀ isoforms and the TCR. Second, incubation of cells with phenanthroline diminished the proportion of degraded high pI CD3⑀ isoforms, but also the ability of the cells to deliver early TCR activation signals. Third, cells expressing mutant CD3⑀ chains lacking N-terminal acid residues showed facilitated recognition by antibody YCD3-1 and enhanced TCR-mediated activation. Furthermore, the binding avidity of antibody YCD3-1 was different in distinct thymus populations. These results suggest that changes in CD3⑀ N-terminal chains might help to fine-tune the response of the TCR to its ligands in distinct activation situations or in thymus selection.

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Mechanisms of H4/ICOS costimulation: effects on proximal TCR signals and MAP kinase pathways

et al. 2002

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H4/ICOS is a costimulatory molecule related to CD28. Its effects on early TCR signals have been analyzed in mouse CD4 + Th2 cells, expressing H4/ICOS at higher levels than Th1 clones. Anti-H4/ICOS antibodies strongly enhanced CD3-mediated tyrosine phosphorylation of ZAP-70,´, or Vav, as well as extracellular signal-regulated kinase (ERK), Jun Nterminal kinase (JNK) and p38 MAP kinase activation in these cells. The association of phosphoinositide 3-kinase (PI-3K) to H4/ICOS was enhanced by H4/ICOS cross-linking, and PI-3K inhibitors inhibited ERK and JNK activation and IL-4/IL-10 secretion, but not p38 MAP kinase or ZAP-70 activation. H4/ICOS-mediated activation of JNK, but not ERK or p38, is partially dependent on the expression of CD4 by the cells, whereas H4/ICOS costimulation is partially independent on CD28 expression. Cytochalasin D, an inhibitor of actin polymerization, inhibited ZAP-70, MAP kinase activation, or IL-4/IL-10 secretion. Neither cyclosporin A nor inhibitors of PKC produced detectable inhibition of ZAP-70 phosphorylation or MAP kinase activation in these Th2 cells. Cyclosporin A strongly inhibited IL-4, but not IL-10 secretion. ERK or JNK inhibitors partially inhibited IL-4 and IL-10 secretion, while PKC or p38 inhibitors had no significant effects on IL-4 or IL-10 secretion. Taken together, our data show clear similarities of costimulation mechanisms between H4/ICOS and CD28 during the early steps of TCR activation.

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Variability of invariant mouse CD3ε chains detected by anti-CD3 antibodies

Cited by 9 publications

References 27 publications

Heterogeneous CD3 Expression Levels in Differing T Cell Subsets Correlate with the In Vivo Anti-CD3–Mediated T Cell Modulation

Heterogeneous CD3 Expression Levels in Differing T Cell Subsets Correlate with the In Vivo Anti-CD3–Mediated T Cell Modulation

Loss of N-terminal Charged Residues of Mouse CD3ɛ Chains Generates Isoforms Modulating Antigen T Cell Receptor-mediated Signals and T Cell Receptor-CD3 Interactions

Mechanisms of H4/ICOS costimulation: effects on proximal TCR signals and MAP kinase pathways

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