The role of FOXP3 in human CD4+CD25+ regulatory T cell phenotype and function
Bibliographic record
Abstract
Naturally occurring CD4+CD25High regulatory T cells (nTreg) have emerged as an essential component of self-tolerance. These cells arise in the thymus and represent 1-10% of CD4+ T cells in humans and mice. They constitutively express the FOXP3 transcription factor. The importance of FOXP3 for Treg cell differentiation and function is illustrated by the Immune-dysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) syndrome; a rare and severe systemic autoimmune disorder caused by mutations in the FOXP3 gene. Treg cell defects are suspected to underlie most other human autoimmune diseases. However the characterization of human nTreg cells has been hindered by the failure to discriminate them from other CD4+ T cells expressing similar markers in states of inflammation, as FOXP3 is expressed by non-suppressive T effector (Teff) cells upon activation. Thus the functional correlates of FOXP3 expression in human Treg cells are ill-defined. We hypothesize that human CD4+CD25HighFOXP3+ T cells represent a heterogeneous population comprised of several Treg and T cell subsets in which the expression of FOXP3 has different functional and phenotypic outcomes. Using a novel single-cell cloning approach, we show that indeed about 30% of memory FOXP3+ T cells are not suppressive, thus revealing a functional heterogeneity amongst CD4+CD25High T cells. These non-suppressive cells are phenotypically identical to their suppressive counterparts, but are found to down-regulate FOXP3 upon activation. By examining the transcriptome of these unstable FOXP3+ T cells, we show that they constitute a genuine, Treg-related, T cell subset, endowed with a specific gene expression signature. Moreover, we find evidence that the stability of the Treg lineage and FOXP3 expression are orchestrated by a higher-level of T-helper cell lineage regulation. Finally, we show that the IPEX-derived A384T mutation in FOXP3 abrogates the capacity of FOXP3 to elicit the suppressive function of Treg cells, while preserving its ability to control their phenotype. We thus provide the first demonstration of a functional dichotomy in the role of FOXP3 in human Treg cells. In conclusion, we demonstrate that FOXP3 is not an absolute marker of suppressive function in human T cells, precluding its sole use as a clinical marker for the monitoring of immunoregulation. Furthermore, we delineate subsets enclosed within FOXP3+ T cells which vary in function and stability, and characterize the hallmarks of these unstable FOXP3+ T cells. These findings will allow for the exploration of their contribution to immune homeostasis, and of their defects in autoimmune disorders.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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".