The inducible costimulator (ICOS) potentiates TCR-mediated calcium mobilization through Lck (IRM10P.749)
Bibliographic record
Abstract
Abstract It was previously shown that T cell costimulatory receptor ICOS plays an important role in inducing acute graft-versus-host disease (GVHD) in murine models. Although ICOS potentiates TCR-mediated phosphoinositide 3-kinase (PI3K) activation and intracellular calcium mobilization, relative roles of each signaling pathway in GVHD remains to be clarified. Using a knock-in strain of mice in which ICOS selectively lost the ability to activate PI3K, we have shown that T cells utilize PI3K-independent ICOS signaling pathways to induce GVHD. This led us to hypothesize that ICOS-Ca2+signaling pathways play important roles in GVHD. Through site-directed mutagenesis and flow cytometric analysis of calcium fluxing capacities of mutant ICOS proteins, we discovered a membrane proximal triple lysine motif in the ICOS cytoplasmic tail that is essential in inducing Ca2+ flux. We also have genetic and biochemical evidence that the Src family kinase Lck plays a crucial role in ICOS-mediated Ca2+signaling through the activation of ZAP-70 and PLCγ1. Moreover, ICOS appears to utilize different mechanisms than CD28 to potentiate TCR-mediated Ca2+ flux suggesting a synergy between the two related T cell costimulators. Thus our study identified ICOS-Lck-PLCγ1 signaling axis in T cell calcium signaling. Based on these, we aim to define the role of ICOS-Ca2+ signaling in GVHD by generating ICOS mutant mice with selective defect in Ca2+ signaling.
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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) | 0.002 | 0.000 |
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".