The inverse agonist activity of soluble CTLA-4 ligands requires oligomerization of this receptor and CD28 expression (88.26)
Bibliographic record
Abstract
Abstract CTLA-4 can inhibit or activate T cells depending on the ligand it engages. We have shown that CTLA-4 ligation with a bi-specific in-tandem single chain Fv, known as 24:26, can activate CTLA-4-expressing primary human T cells in the absence of TCR and CD28 engagement. To understand the basis of such an inverse agonist activity, we examined the requirements for CTLA-4-mediated T cell activation. We observed that 24:26 and soluble B7.1 Ig, but not B7 molecules on APCs, induced the formation of a unique CTLA-4 oligomer that disappeared from the soluble cell lysate fraction and subsequently appeared in the insoluble cellular fraction. Oligomerization occurred upon ligation of CTLA-4 homodimers and was necessary but not sufficient for T cell activation. The inverse agonist activity of these soluble ligands required the cytoplasmic domain of CTLA-4 since CTLA-4 molecules lacking this domain did not induce T cell activation. CD28 expression was necessary for the inhibitory and activating functions of CTLA-4 suggesting a functional interaction between these two receptors. Understanding the functional responses to soluble ligands of costimulatory receptors is important in the wake of the side effects observed with CD28 superagonists. Our data indicates that the biological effect of soluble ligands of CTLA-4 will be determined by the oligomerization of this receptor. Supported by the Canadian Institutes of Health Research.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".