Genital herpes, caused by herpes simplex virus 2 (HSV-2), remains a prevalent sexually transmitted infection with no available vaccine. Effective local immunity, mediated in part by tissue-resident memory T cells (TRM cells) and luminal antibodies, provides immediate viral control. Here, we developed bioactive enhanced adjuvant chemokine oligonucleotide nanoparticles (BEACONs) formed via electrostatic interactions between CpG oligodeoxynucleotides (CpG ODNs) and the chemokine CXCL9. This adjuvant enhances antigen-presenting cell engagement and innate immune signaling, promotes CD8 T cell recruitment, and reduces local neutrophilic inflammation relative to CpG ODNs. After intramuscular priming with HSV-2 glycoprotein-encoding messenger RNA-lipid nanoparticles, vaginal boosting with cognate recombinant glycoprotein and BEACONs improved protection against HSV-2 by increasing local CD8 TRM cell populations and mucosal antibody responses. Vaccine-mediated protection required local delivery of both antigen and adjuvant and was reduced by CD8 T cell or B cell depletion. These findings support engineered mucosal adjuvants for vaccines targeting genital herpes and other sexually transmitted infections.

Alopecia areata (AA) is an immune-mediated hair loss disorder characterized by the infiltration of immune cells, including clonally expanded CD8+ T cells into lesional skin. To explore the link between CD8+ T cell clonality and disease pathogenicity, we conducted single-cell RNA and T cell receptor (TCR) sequencing in the C3H/HeJ mouse model of AA. We analyzed T cells derived from skin and skin-draining lymph nodes to capture both the end-organ and the site of antigen priming and found striking hyper-expansion of T cell clones associated with disease onset. Using the hyperexpanded CD8+ TCR sequences, we generated TCR retrogenic mice engineered to express a single clonotypic T cell population, applied CRISPR-Cas9 to engineer these TCR sequences within CD8+ T cells, and performed depletion experiments to demonstrate that expanded CD8+ T cell clones are sufficient to initiate disease, establishing a causal relationship between CD8+ T cell clonality and pathogenicity in disease.
Copyright © 2025. Published by Elsevier Inc.

Mutations that negatively impact mitochondrial function are highly prevalent in humans and lead to disorders with a wide spectrum of disease phenotypes, including deficiencies in immune cell development and/or function. Previous analyses of mice with a hepatocyte-specific cytochrome c oxidase (COX) deficiency revealed an unexpected peripheral blood leukopenia associated with splenic and thymic atrophy. Here, we use mice with a hepatocyte-specific deletion of the COX assembly factor Sco1 to show that metabolic defects extrinsic to the hematopoietic compartment lead to a pan-lymphopenia represented by severe losses in both B and T cells. We further demonstrate that immune defects in these mice are associated with the loss of bone marrow lymphoid progenitors common to both lineages and early signs of autoantibody-mediated autoimmunity. Our findings collectively identify hepatocyte dysfunction as a potential instigator of immunodeficiency in patients with congenital mitochondrial defects who suffer from chronic or recurrent infections.
© 2025 The Author(s).

Public health alarm concerning the emerging fungus Candida auris is fueled by its antifungal drug resistance and propensity to cause deadly outbreaks. Persistent skin colonization drives transmission and lethal sepsis although its basis remains mysterious. We compared the skin colonization dynamics of C. auris with its relative C. albicans , quantifying skin fungal persistence and distribution and immune composition and positioning. C. auris displayed a higher propensity to colonize hair follicles and avidly bound to human hair. While C. albicans triggered an effective sterilizing type 3/17 antifungal immune response driven by IL-17A/F-producing lymphocytes, C. auris triggered a type 1, IFNγ-driven immune response targeting hair follicles. Rather than promoting fungal clearance, IFNγ enhanced C. auris skin colonization by acting directly on keratinocytes impairing epithelial barrier integrity and repressing antifungal defense programs. C. auris exploits focal skin immune responses to create a niche for persistence in hair follicles.

Fatty acid metabolites, produced by cytochrome P450 enzymes and soluble epoxide hydrolase (sEH), regulate inflammation. Here, we report that the transforming growth factor β (TGF-β)-induced polarization of macrophages to a pro-resolving phenotype requires Alk5 and Smad2 activation to increase sEH expression and activity. Macrophages lacking sEH showed impaired repolarization, reduced phagocytosis, and maintained a pro-inflammatory gene expression profile. 11,12-Epoxyeicosatrienoic acid (EET) was one altered metabolite in sEH-/- macrophages and mimicked the effect of sEH deletion on gene expression. Notably, 11,12-EET also reduced Alk5 expression, inhibiting TGF-β-induced Smad2 phosphorylation by triggering the cytosolic translocation of the E3 ligase Smurf2. These findings suggest that sEH expression is controlled by TGF-β and that sEH activity, which lowers 11,12-EET levels and promotes TGF-β signaling by metabolizing 11,12-EET to prevent Alk5 degradation. Thus, an autocrine loop between sEH/11,12-EET and TGF-β1 regulates macrophage function.
© 2024 The Author(s).