Human Regulatory T Cell Potential for Tissue Repair Via IL-33/ST2 and Amphiregulin
Notice bibliographique
Résumé
Regulatory T cell (Treg)-based therapy is a promising curative approach for allograft rejection. Beyond their effects on immune cells, emerging evidence suggests that Tregs have direct effects on tissue repair. Specifically, Tregs in mice promote tissue repair after infection or injury by secreting the EGF family member amphiregulin (AREG) under the control of alarmin IL-33 and its receptor ST2. We investigated the potential of human blood Tregs to mediate tissue repair via the IL-33/ST2 axis and AREG production. AREG expression was measured by flow cytometry in blood Tregs (flow-sorted as CD4+CD25+CD127-) stimulated with PMA and ionomycin. Human Tregs could produce AREG ex vivo, upregulated by TCR activation, but at a lower proportion than their Tconv counterparts (flow-sorted as CD4+CD25-CD127+). AREG expression was enriched in non-effector Tregs (CD39-, CCR4-, TIGIT-), a phenotype maintained after TCR activation. Moreover, AREG production potential was lost upon Treg proliferation and differentiation, suggesting that AREG production may comprise a distinct modality of human Tregs. In contrast to reports from mouse Tregs, IL-33 did not affect human blood Treg production of AREG. However, ST2 was undetectable in blood Tregs ex vivo and after activation. To more accurately measure human ST2 expression, we used phage display to generate a series of anti-ST2 antibodies. Experiments in transfected and endogenous ST2+ cells revealed several candidate antibodies that were superior to commercially available options for flow cytometric detection of human ST2. Investigations to define the tissue localization and biology of human ST2+ Tregs are in progress. Meanwhile, because of the importance of IL-33 signalling in promoting both the function and maintenance of mouse ST2+ Tregs in tissues, we sought to generate a plentiful source of human ST2+ Tregs to evaluate their potential as a cell therapy. Human blood naïve Tregs (flow-sorted as CD4+CD25+CD127-CD45RA+) were engineered to overexpress ST2 and expanded for 12 days with artificial antigen-presenting cells, anti-CD3, and IL-2. ST2 overexpression conferred IL-33 responsiveness, as determined by signal transduction and increased proliferation. IL-33 upregulated AREG in a TCR-independent manner on ST2-engineered Tregs, suggesting that the tissue repair capacity of human Tregs may be controlled innately. Overall, human Treg expression of AREG is associated with an innate-like program, potentially regulated by IL-33 and uncoupled from classical TCR-dependent Treg effector functions. Knowledge of the mechanisms by which human Tregs mediate tissue repair and the signals controlling this process will help delineate their therapeutic potential when used as a cell therapy. Thus, future investigations will focus on the tissue repair capacity of human Treg-derived AREG in vitro, as well as the in vivo functions of ST2-engineered Tregs in a humanized allotransplant model. CIHR Doctoral Research Award. CIHR Foundation Grant.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».