Oropharyngeal candidiasis (OPC) is an opportunistic infection caused by Candida albicans. IL-17-mediated immunity driven by Th17 cells plays a crucial role in defense against this infection. However, the location and mechanism by which the Th17 immune response is induced during OPC remain unclear. Here, we show that C. albicans in the gut enhances protection against OPC. Intestinal C. albicans is taken up by the mucosal immune system and triggers a systemic C. albicans-responsive Th17 cell response. Upon oral infection with C. albicans, these Th17 cells migrate from the gut to the oral region and accumulate in the tongue tissue, resulting in antifungal immune responses. The pathobiont-reactive Th17 cells developed in the gut strongly provide IL-17A not only locally in the mouth but also systemically in the serum upon OPC. Our findings highlight that fungal pathogen-responsive Th17 cells in the gut-mouth axis enhance protection against OPC.
© 2025 The Author(s).

Cyclosporin A (CSA) and tacrolimus (TAC) suppress T-cell activation and subsequent proliferation by inhibiting calcineurin. Though they have the same target, CSA and TAC have quite different molecular structures, indicating quantitative and/or qualitative differences in their effects.
CD28 is a costimulatory molecule that enhances T-cell activation. It has also been shown to attenuate calcineurin inhibitors. In this study, we compared the CD28-mediated resistance of CD4+ T cells to those calcineurin inhibitors and tried to predict CD28's impact on infectious diseases.
CD4+ T-cell proliferation was induced with anti-CD3 mAb in the presence or absence of anti-CD28 mAb in vitro. CSA or TAC was added at various concentrations, and the half-maximal inhibitory concentration on CD4+ T-cell proliferation was determined. Effects of lipopolysaccharide (LPS) on dendritic cells (DCs) and CD4+ T-cell proliferation were also evaluated in vitro.
Anti-CD28 mAb conferred CD4+ T cells with resistance to both CSA and TAC, and CD28's effect on the latter was approximately twice that on the former. LPS induced expression of CD28 ligands CD80/86 on DCs. The addition of LPS to culture containing DCs seemed to make CD4+ T cells slightly resistant to TAC but not to CSA. However, its effect on the former was very weak under our experimental conditions.
CD28 attenuated TAC more strongly than CSA. Although LPS did not demonstrate strong enough resistance in our in vitro model, TAC might maintain a better antibacterial immune response than CSA in clinical use.

Phosphatase and tensin homolog (PTEN) is vital for B cell development, acting as a key negative regulator in the PI3K signaling pathway. We used CD23-cre to generate PTEN-conditional knockout mice (CD23-cKO) to examine the impact of PTEN mutation on peripheral B cells. Unlike mb1-cre-mediated PTEN deletion in early B cells, CD23-cKO mutants exhibited systemic inflammation with increased IL-6 production in mature B cells upon CpG stimulation. Inflammatory B cells in CD23-cKO mice showed elevated phosphatidylinositol 3-phosphate [PI(3)P] levels and increased TLR9 endosomal localization. Pharmacological inhibition of PI(3)P synthesis markedly reduced TLR9-mediated IL-6. Single-cell RNA-sequencing (RNA-seq) revealed altered endocytosis, BANK1, and NF-κB1 expression in PTEN-deficient B cells. Ectopic B cell receptor (BCR) expression on non-inflammatory mb1-cKO B cells restored BANK1 and NF-κB1 expression, enhancing TLR9-mediated IL-6 production. Our study highlights PTEN as a crucial inflammatory checkpoint, regulating TLR9/IL-6 axis by fine-tuning PI(3)P homeostasis. Additionally, BCR downregulation prevents the differentiation of inflammatory B cells in PTEN deficiency.
© 2024 The Author(s).

Abstract The severity of allergic asthma is driven by the balance between allergen-specific T regulatory (Treg) and T helper (Th)2 cells. However, it is unclear whether specific subsets of conventional dendritic cells (cDCs) promote the differentiation of these two T cell lineaeges. We have identified a subset of lung resident type 2 cDCs (cDC2s) that display high levels of CD301b and have potent Treg-inducing activity ex vivo. Single cell RNA sequencing and adoptive transfer experiments show that during allergic sensitization, many CD301b+ cDC2s transition in a stepwise manner to CD200+ cDC2s that selectively promote Th2 differentiation. GM-CSF augments the development and maintenance of CD301b+ cDC2s in vivo, and also selectively expands Treg-inducing CD301b+ cDC2s derived from bone marrow. Upon their adoptive transfer to recipient mice, lung-derived CD301b+ cDC2s confer immunological tolerance to inhaled allergens. Thus, GM-CSF maintains lung homeostasis by increasing numbers of Treg-inducing CD301b+ cDC2s.

Undifferentiated monocytes can be loaded with tumor antigens (Ag) and administered intravenously to induce antitumor cytotoxic T lymphocyte (CTL) responses. This vaccination strategy exploits an endogenous Ag cross-presentation pathway, where Ag-loaded monocytes (monocyte vaccines) transfer their Ag to resident splenic dendritic cells (DC), which then stimulate robust CD8 + CTL responses. In this study, we investigated whether monocyte vaccination in combination with CDX-301, a DC-expanding cytokine Fms-like tyrosine kinase 3 ligand (Flt3L), could improve the antitumor efficacy of anti-programmed cell death (anti-PD-1) immune checkpoint blockade. We found that Flt3L expanded splenic DC over 40-fold in vivo and doubled the number of circulating Ag-specific T cells when administered before monocyte vaccination in C57BL/6 mice. In addition, OVA-monocyte vaccination combined with either anti-PD-1, anti-programmed cell death ligand 1 (anti-PD-L1), or anti-cytotoxic T lymphocyte antigen-4 (anti-CTLA-4) suppressed subcutaneous B16/F10-OVA tumor growth to a greater extent than checkpoint blockade alone. When administered together, OVA-monocyte vaccination improved the antitumor efficacy of Flt3L and anti-PD-1 in terms of circulating Ag-specific CD8 + T cell frequency and inhibition of subcutaneous B16/F10-OVA tumor growth. To our knowledge, this is the first demonstration that a cancer vaccine strategy and Flt3L can improve the antitumor efficacy of anti-PD-1. The findings presented here warrant further study of how monocyte vaccines can improve Flt3L and immune checkpoint blockade as they enter clinical trials.
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