BRIEF RESEARCH REPORT article
Front. Immunol.
Sec. Autoimmune and Autoinflammatory Disorders: Autoinflammatory Disorders
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1599985
This article is part of the Research TopicThe Innate Immune System as a Driver of Diabetes and its ComplicationsView all 5 articles
Sex-Specific Metabolic Effects of Treg Expansion in db/db Mice
Provisionally accepted
- 1Vall d'Hebron Research Institute (VHIR), Barcelona, Spain
- 2Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
- 3Autonomous University of Barcelona, Barcelona, Catalonia, Spain
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Introduction: Type 2 diabetes mellitus (T2D) is characterized by chronic, low-grade inflammation and immune dysregulation, contributing to insulin resistance and metabolic complications. Regulatory T cells (Tregs) are key modulators of immune homeostasis, and their therapeutic expansion has shown promise in limiting inflammation. Here, we investigated whether in vivo Treg expansion could modulate metabolic and inflammatory responses in T2D in a sex-specific manner. Methods: Male and female db/db and db/+ mice received intraperitoneal injections of IL-2/anti-IL-2 (JES6-1) complexes for six weeks to induce endogenous Treg expansion. Body weight, blood glucose, and insulin levels were monitored to calculate HOMA-IR. Plasma inflammatory and anti-inflammatory mediators (CRP, adiponectin, IL-10, IL-13, CCL3) were quantified by bead-based immunoassays. Hepatic triglycerides and gene expression of Foxp3, F4/80, Pparγ, Il10 and Il13 were analyzed by biochemical assays, western blot, and RT-qPCR. Results: Treg expansion reduced weight gain in db/db mice independently of food intake. Female mice displayed lower HOMA-IR, decreased CRP, and increased adiponectin, IL-10, and IL-13 levels, whereas males showed limited improvement. Hepatic triglycerides and F4/80 expression were reduced after Treg expansion, with restored Foxp3 and elevated Il10/Il13 expression, indicating diminished hepatic inflammation. Conclusion: Endogenous Treg expansion exerts sex-specific metabolic and anti-inflammatory benefits in db/db T2D mice, with females showing greater improvements in insulin resistance, inflammation, and hepatic lipid metabolism. These findings support Treg-based immunomodulation as a potential therapeutic approach for T2D and emphasize the need for sex-specific considerations in future research.
Keywords: sex differences, regulatory T cells, Immunomodulation, Inflammation, Type 2diabetes, Metabolism
Received: 25 Mar 2025; Accepted: 13 Oct 2025.
Copyright: © 2025 Pérez-Martínez, Hernández, Simó and Llorián-Salvador. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Maria Llorián-Salvador, m.lloriansalvador@qub.ac.uk
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