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BCG vaccination potentiates oxidative phosphorylation in neonatal myeloid-derived suppressor cells

ABSTRACT: BCG vaccination has well‑documented off‑target effects in early life, but the underlying molecular mechanisms remain incompletely understood. This study investigated whether BCG reprograms neonatal myeloid‑derived suppressor cells (MDSCs) through oxidative phosphorylation (OXPHOS). Neonatal mice (3-4 days old) received a single subcutaneous injection of BCG (5×10⁵ CFU) or PBS. Splenic monocytic (M‑) and polymorphonuclear (PMN‑) MDSCs were analyzed using single‑cell RNA‑seq, bulk RNA‑seq, qRT‑PCR, flow cytometry, and Seahorse metabolic analysis. Immunosuppressive function was assessed with T‑cell proliferation assays in the presence or absence of oligomycin, an OXPHOS inhibitor. BCG vaccination significantly increased the expression of OXPHOS‑related genes (Ndufab1, Sdhd, Uqcrfs1, Cox4i) and mitochondrial mass in both MDSC subsets. Seahorse analysis revealed a higher oxygen consumption rate in BCG‑exposed PMN‑MDSCs. Functional assays showed that BCG impaired MDSC‑mediated T‑cell suppression; oligomycin treatment partially restored this suppressive capacity. Together, these findings indicate that BCG‑induced OXPHOS potentiation contributes to the loss of MDSC immunosuppressive function in neonatal mice, providing a molecular mechanism for the non‑specific immunomodulatory effects of BCG vaccination early in life.

ORGANISM(S): Mus musculus

PROVIDER: GSE330508 | GEO | 2026/09/02

REPOSITORIES: GEO

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Project description:Myeloid-derived suppressor cells (MDSCs) are key players in immune evasion, tumor progression and metastasis. MDSCs accumulate under various pathological states, and fall into two functionally and phenotypically distinct subsets: polymorphonuclear (PMN)-MDSCs and monocytic (M)-MDSCs. These subsets have been studied extensively in humans and mice, yet to date no study has identified MDSC subsets in dogs with spontaneous tumors. As dogs are an excellent model for human tumor development and progression, we set out to identify PMN-MDSCs and M-MDSCs in clinical canine oncology patients. We identified MDSCs as hypodense MHC class II-CD5-CD21-CD11b+ cells and show for the first time that they can also be subdivided into polymorphonuclear (CADO48A+CD14-) and monocytic (CADO48A-CD14+) subsets. The transcriptomic signatures of PMN-MDSCs and M-MDSCs are distinct from each other and from those of conventional polymorphonuclear (PMN) and monocytic cells, respectively. Notably, bioinformatic analyses reveal a statistically significant similarity between canine and previously published human MDSC gene expression patterns. As in humans, peripheral blood frequencies of canine PMN-MDSCs and M-MDSCs are significantly different in dogs with cancer compared to healthy control dogs (PMN-MDSCs: p < .001; M-MDSCs: p < .01). Furthermore, a comparison of our canine MDSC RNA-seq data with transcriptomic results previously published for human and murine MDSCs highlights five commonly upregulated genes in PMN-MDSCs in all species, suggesting that these genes are evolutionarily conserved and functionally important. Interestingly, one gene has previously been implicated in PMN-MDSC function (MMP8), but four genes (LTF, LCN2, CAMP, EBP41L3) are novel in the context of PMN-MDSCs. Our findings therefore demonstrate for the first time that dogs have two distinct populations of MDSCs, characterized by specific phenotypic and transcriptomic signatures that share key features of human MDSC subsets. Importantly, by leveraging the power of evolution, we have identified additional conserved genes in PMN-MDSCs of multiple species which may play a role in MDSC function. Our findings therefore validate the dog as a model for studying MDSCs in the context of cancer.

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BCG vaccination potentiates oxidative phosphorylation in neonatal myeloid-derived suppressor cells

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