Yohei Sato

Regulatory T cells (Tregs) maintain immune homeostasis in vivo. Similar to conventional T cells (Tconvs), Tregs are divided into naïve and memory cells. Tregs have unique metabolic properties, including enhanced oxidative phosphorylation. The lipidomic profiles of human Tregs have been studied previously; however, those of naïve and memory Tregs have not yet been consistently compared. Thus, in the present study, we used a combined transcriptomic and lipidomic analysis to assess the metabolic features of human naïve and memory Tregs upon activation. Using transcriptomic analysis, we identified distinct gene expression profiles in naïve and memory Tregs compared with those in Tconvs. Upon TCR stimulation, memory Tregs showed a lipidomic profile distinct from that of memory Tconvs, whereas the lipidomic profiles of naïve Tregs were similar to those of naïve Tconvs. Furthermore, upon TCR stimulation, memory Tregs expressed triglycerides (TGs) that were more enriched in monounsaturated fatty acids and polyunsaturated fatty acids (PUFAs) than those of memory Tconvs. However, memory Tconvs also had higher PUFA-TG levels than naïve Tconvs and Tregs after TCR stimulation, although their levels remained lower than those in memory Tregs. These findings suggest PUFA-TGs could be a marker of memory Tregs. In turn, higher frequency of memory cells within the Treg population may also contribute to the observed enrichment of PUFA-TGs in Tregs upon TCR activation. Our study demonstrated unique transcriptomic and lipidomic profiles and enhanced lipogenesis in memory Tregs upon TCR stimulation.

Background: Chronic rhinosinusitis with nasal polyp (CRSwNP) is a heterogeneous Type 2 inflammatory disease characterized by enhanced eosinophilic infiltration. Both innate and adaptive immunity are involved in the onset and progression of CRSwNP. Increased serum leptin levels are associated with various allergic conditions; however, the biological role of leptin in allergic immune cells requires further investigation. Objective: To investigate the effects of leptin on immune cells, including eosinophils, basophils, and mast cells, in CRSwNP. Methods: Leptin was used to stimulate eosinophils and eosinophilic cell lines, followed by analyses of gene expression, migration, and angiogenic capacity. Immunometabolic profile of CRSwNP, serum leptin, and galectin‐10 levels were analyzed in conjunction with the gene expression profiles of nasal polyps. Furthermore, the biological effects of leptin on eosinophils were assessed using RNA sequencing and functional analyses, including a transwell migration assay and an angiogenesis assay via co‐culture with human umbilical vein endothelial cells (HUVEC). Results: Increased serum leptin and galectin‐10 levels were associated with Type 2 inflammatory markers and correlated with CRSwNP severity. RNA sequencing revealed upregulation of chemokine ligands in eosinophilic cell lines. Leptin induced plasminogen activator inhibitor 1 (PAI‐1) expression in eosinophils but not in basophils or neutrophils. Leptin pretreatment substantially enhanced migration toward both C–C motif chemokine ligand (CCL) 11 and CCL26 in eosinophilic cell lines. The leptin‐primed eosinophilic cell line promoted angiogenesis, as demonstrated in co‐culture with HUVECs. Conclusion: Leptin promotes eosinophil migration and angiogenesis, potentially via chemokine ligands and PAI‐1 induction, and may promote CRSwNP progression under a Type 2 inflammatory milieu.