A role for vitamin D in immune modulation and in cancer has been suggested. In this work, we report that mice with increased availability of vitamin D display greater immune-dependent resistance to transplantable cancers and augmented responses to checkpoint blockade immunotherapies. Similarly, in humans, vitamin D–induced genes correlate with improved responses to immune checkpoint inhibitor treatment as well as with immunity to cancer and increased overall survival. In mice, resistance is attributable to the activity of vitamin D on intestinal epithelial cells, which alters microbiome composition in favor of Bacteroides fragilis , which positively regulates cancer immunity. Our findings indicate a previously unappreciated connection between vitamin D, microbial commensal communities, and immune responses to cancer. Collectively, they highlight vitamin D levels as a potential determinant of cancer immunity and immunotherapy success.

An antiviral Dicer defends stem cells: Stem cells have a pivotal role in maintaining tissue architecture, integrity, and renewal. Poirier et al. demonstrate that mammalian stem cells can protect themselves from some RNA viruses by expressing an alternatively spliced isoform of the enzyme Dicer called aviD, which potentiates antiviral RNA interference (see the Perspective by Shahrudin and Ding). aviD acts by cleaving long, base-paired viral RNAs to generate small interfering RNAs that direct the sequence-specific cleavage of homologous viral RNAs. This process is reminiscent of that in insects and worms, which also use Dicer-dependent RNA interference in antiviral defense, and contrasts with mammalian differentiated cells, which generally rely on the interferon system to combat virus infection. Science , abg2264, this issue p. 231 ; see also abj5673, p. 160

Conventional dendritic cells (cDCs) include functionally and phenotypically diverse populations, such as cDC1s and cDC2s. The latter population has been variously subdivided into Notch-dependent cDC2s, KLF4-dependent cDC2s, T-bet⁺ cDC2As and T-bet⁻ cDC2Bs, but it is unclear how all these subtypes are interrelated and to what degree they represent cell states or cell subsets. All cDCs are derived from bone marrow progenitors called pre-cDCs, which circulate through the blood to colonize peripheral tissues. Here, we identified distinct mouse pre-cDC2 subsets biased to give rise to cDC2As or cDC2Bs. We showed that a Siglec-H⁺ pre-cDC2A population in the bone marrow preferentially gave rise to Siglec-H⁻ CD8α⁺ pre-cDC2As in tissues, which differentiated into T-bet⁺ cDC2As. In contrast, a Siglec-H⁻ fraction of pre-cDCs in the bone marrow and periphery mostly generated T-bet⁻ cDC2Bs, a lineage marked by the expression of LysM. Our results showed that cDC2A versus cDC2B fate specification starts in the bone marrow and suggest that cDC2 subsets are ontogenetically determined lineages, rather than cell states imposed by the peripheral tissue environment.

Effective T cell–dependent immunity to influenza A virus requires recruitment of cDC progenitors to foci of infection via CCR2.

Innate immune receptors often induce activation of conventional dendritic cells (cDCs) and enhance antigen (cross-)presentation, favouring immune responses. DNGR-1 (CLEC9A), a receptor expressed by type 1 cDCs (cDC1s) and implicated in immune responses to viruses and cancer, recognises F-actin exposed on dead cell remnants and promotes cross-presentation of associated antigens. Here, we show that recruitment of phosphatase SHIP1, a process governed by a single amino acid residue adjacent to the signalling motif of the receptor, partly explains how DNGR-1 fails to trigger cDC1 activation in vitro. Substituting this residue converts DNGR-1 into an activating receptor but decreases induction of cross-presentation of dead cell-associated antigens. Introducing the reverse mutation into the related receptor Dectin-1 impairs its activation capacity while enhancing its ability to promote cross-presentation. These findings reveal a functional trade-off in receptor signalling and suggest that DNGR-1 has evolved to prioritise antigen cross-presentation over cellular activation, possibly to minimise inflammatory responses to dead cells.

Background: Allergic rhinitis (AR) is an increasingly common chronic inflammatory condition of the nasal mucosa. While conventional anti‐allergy treatments are widely used, they can come with side effects and are not always effective. As a result, AR remains a significant concern for many millions of people worldwide, affecting quality of life and social functioning. Objective: To investigate clinical evidence for the role of probiotics and postbiotics in reducing AR symptoms. Methods: In this single‐centre, randomized, double‐blind, placebo‐controlled clinical trial, 72 adults aged 18–60 years with moderate–severe AR, taking first‐line medication, were studied. The primary outcome of the trial was to determine the effects of supplementation with the probiotic Bifidobacterium longum CECT 7347 (PRO) and the heat‐treated postbiotic of the same strain (POST) on symptoms associated with AR as assessed using the Combined Symptom and Medication Score (CSMS). The secondary outcomes of the study assessed the effects of the interventions over: quality of life (rhinitis quality of life questionnaire [RQLQ]), systemic immune response, local immune response, and faecal microbiota composition. Results: Statistically significant reduction in total CSMS after 8 weeks of supplementation was observed in the POST group compared to placebo control (CON) ( p = 0.022), showing on average a 0.6 greater reduction than placebo (CI: 0.09–1.12), equivalent to a 33.15% greater reduction and exceeding the World Allergy Organization's threshold for minimal clinically significant efficacy. Conclusion: POST intake for 8 weeks was associated with a statistically significant reduction of total CSMS compared to placebo. There was also improvement in RQLQ parameters when compared to baseline. PRO intake for 8 weeks resulted in non‐significant beneficial effects on AR‐related symptoms. Trial Registration: ClinicalTrials.gov Identifier: NCT05208528