Signaling Through gp130 Compromises Suppressive Function in Human FOXP3+ Regulatory T Cells
Bibliographic record
Abstract
The CD4+FOXP3+ regulatory T cell (Treg) subset is an indispensable mediator of immune tolerance. High and stable expression of the transcription factor FOXP3 is considered a hallmark feature of Treg cells. Using a single-cell cloning strategy that allows the discrimination between activated Teff contaminants and bona fide FOXP3-expressing Treg clones, we have recently shown that the human FOXP3+ Treg population is functionally heterogeneous, containing a sizeable proportion of clones with an impaired capacity to suppress Teff cells despite exhibiting the hallmark surface phenotype of functional Treg cells. We have further demonstrated that this FOXP3-positive, suppression-negative (FPSN) subpopulation, resembles its FOXP3-positive, suppression-positive (FPSP) counterpart in the demethylation status of the Treg-specific demethylated region (TSDR) of the FOXP3 locus, as well as in the global Treg gene expression signature. These findings indicated that these non-suppressive FOXP3+ cells likely originate from previously functional Treg cells. There are currently no markers to delineate these dysfunctional FOXP3+ cells, and their prevalence and potential role in autoimmunity remains unknown. This study aims to characterize the factors that drive loss of suppressive function in human Treg cells, and to identify surface markers of dysfunctional Treg cells. We show that high expression of the IL-6 family cytokine receptor subunit gp130 identifies Treg cells with reduced suppressive capacity ex vivo and in primary FOXP3+ clones. We further show that two gp130-signaling cytokines, IL-6 and IL-27, impair the suppressive capacity of human Treg cells. Finally, we show that gp130 signaling reduces the expression of the transcription factor Helios, whose expression is essential for stable Treg function. These results highlight the role of gp130 in regulating human Treg function, and suggest that modulation of gp130 signaling may serve as a potential avenue for the therapeutic manipulation of human Treg function.
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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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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".