Glucagon-like peptide-1 agonism in combination with low-dose interleukin 2 enhances regulatory T cell suppressive function in vitro

Abstract Objectives Dysregulated immune responses are characterized by pro-inflammatory activated myeloid cells that impair regulatory T cell (Treg) function and drive chronic inflammatory, autoimmune, and neurodegenerative diseases. Suppression of myeloid activation provides the potential to enhance Treg neuroprotective functions. Individually, low-dose interleukin-2 (LD-IL2) and glucagon-like peptide-1 receptor agonists (GLP-1RA) demonstrate promising immunomodulatory effects in preclinical models and clinical trials. The current study evaluates the combination effects of these therapeutic modalities to suppress pro-inflammatory myeloid cells, enhance Treg suppressive functions, and modulate T cell proliferation in vitro. Methods Peripheral monocytes, Tregs, and responder T cells (Tresps) from healthy donors were isolated and co-cultured with single and combination dosing of LD-IL2 (COYA 301) and GLP-1RA (Semaglutide, Exendin-4). Pro-inflammatory myeloid cells were stimulated with lipopolysaccharide (LPS) and interferon-gamma (IFN-γ). Treg suppressive function, cytokines, inflammatory transcripts, and Tresp proliferation suppression assessed from in vitro culture. Results Combination treatment with COYA 301 and GLP-1RA enhanced Treg suppression of IL-6 production by pro-inflammatory myeloid cells, reduced myeloid cell pro-inflammatory transcripts of IL-6 and TNF, and increased anti-inflammatory myeloid marker transcripts of ARG1. Tresp proliferation was more effectively suppressed by the combination than either agent alone. Tregs treated with COYA 301 and GLP-1RA exhibited increased FOXP3, IL2RA/CD25, and CTLA-4 expression, along with enhanced anti-apoptotic BCL-2 and reduced pro-apoptotic BAX transcripts. Conclusions The combination of COYA 301 and GLP-1RA provides additive immunomodulatory effects by enhancing Treg suppressive function, reducing pro-inflammatory signaling, and promoting Treg survival. These findings support the therapeutic potential of this combination in inflammatory and neurodegenerative diseases.