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Low-dose allergen targeting to cDC2 induces long-term protection associated with IL-10+ Foxp3- CD8+ regulatory T cells in mice

ABSTRACT: The prevalence of allergic diseases is rising worldwide. Desensitizing immunotherapy is currently the only available treatment, but it is often ineffective for certain allergies, underscoring the need for new treatments. This study tested whether direct allergen targeting to DC subsets can improve desensitization. An Ovalbumin (OVA)-mediated allergy mouse model was used to compare a Standard desensitization protocol, which is also used in humans, with a novel antibody-OVA fusion protein targeting the conventional cDC1 and cDC2 subsets via their respective receptors CD205 (CD205-Fp) or DCIR2 (DCIR2-Fp). OVA allergy treatment by cDC2 targeting provided long-lasting protection for up to 56 days after desensitization with only nanogram doses of allergen, whereas the Standard therapy protected for only 20 days, requiring microgram doses and repeated injections with Alum adjuvant. CD205-Fp showed no protective effect. Blocking IL-10 either before administering DCIR2-Fp or before allergen challenge completely abolished protection. Standard therapy had moderate effects on CD4+ T cells, with early expansion of IL-10⁺ Foxp3⁻ T regulatory type-1 cells (Tr1), followed by an increase in both IL-10⁺ and IL-10⁻ Foxp3⁺ regulatory T cells (Treg). DCIR2-Fp therapy initially expanded IL-10⁺ and IL-10⁻ Foxp3⁺ Treg, but these levels returned to baseline by day 80. Notably, we identified Foxp3- CD44high CD8⁺ memory Treg as the primary source of IL-10 at day 80. Overall, our data suggest that cDC2 allergen targeting in allergic mice offers a potent, long-lasting IL-10-dependent protective effect.

ORGANISM(S): Mus musculus

PROVIDER: GSE326802 | GEO | 2026/07/28

REPOSITORIES: GEO

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Project description:Mechanisms by which regulatory T (Treg) cells fail to control inflammation in asthma remain poorly understood. We show that a severe asthma-associated polymorphism in the interleukin-4 receptor alpha chain (IL-4RÎ±-R576) biases induced Treg (iTreg) cells towards a T helper 17 (TH17) cell fate. This skewing reflects the recruitment by IL-4RÎ±-R576 of the adaptor protein growth factor receptor-bound protein 2 (GRB2), which drives IL-17 expression by an extracellular signal-regulated kinase-, IL-6- and STAT3-dependent mechanism. We showed that the IL-4RÎ±-R576 mutation elicits TH17 airway responses in vivo, in a house dust mite (HDM)- or ovalbumin (OVA)-driven model of airway inflammation in the mice carry the IL-4RÎ±-R576 mutation (Il4raR576 mice). Treg cell-specific deletion of genes encoding IL-6RÎ± or the master TH17 cell regulator Retinoid-related Orphan Receptor Î³t (RORÎ³t), but not IL-4 and IL-13, protected mice against exacerbated airway inflammation induced by IL-4RÎ±--576. Analysis of lung tissue Treg cells revealed that the expression of IL-17 and the TH17 cell-associated chemokine receptor CCR6 was largely overlapping and highly enriched in Treg and conventional T (Tconv) cells of allergen-treated Il4raR576 mice. To further characterize the subset of IL-17 producing Foxp3+ Treg in the lung of OVA-treated mice we utilized CCR6 as a marker of Treg cells committed towards the TH17 cell lineage to examine their functional, epigenetic and transcriptional profiles. CCR6+Foxp3EGFP+ Treg cells isolated from OVA-sensitized and challenged Il4raR576 mice, by FACS (Fluorescence Activated Cell Sorting) exhibited decreased methylation of the Foxp3 CNS2 locus comparing to CCR6âFoxp3EGFP+ Treg cells from same animals, indicative of decreased stability. They also exhibited profoundly decreased suppressive function as compared to CCR6â WT and CCR6â Il4raR576 counterparts. Transcriptional profiling of CCR6+Foxp3EGFP+ Treg cells revealed increased relative expression in CCR6+ Il4raR576 Treg cells of genes associated with a TH17 cell signature, including Rorc, Ccr6, Il23r, Il17a, Il17f, Il1r1, Nr1d1, Cstl, and Ahr comparing to CCR6âFoxp3EGFP+ Treg cells from same animals. Three CCR6+Foxp3EGFP+ Il4raR576 replicates and four CCR6âFoxp3EGFP+ Il4raR576 Treg replicates (controls) were sampled

Project description:Mechanisms by which regulatory T (Treg) cells fail to control inflammation in asthma remain poorly understood. We show that a severe asthma-associated polymorphism in the interleukin-4 receptor alpha chain (IL-4Rα-R576) biases induced Treg (iTreg) cells towards a T helper 17 (TH17) cell fate. This skewing reflects the recruitment by IL-4Rα-R576 of the adaptor protein growth factor receptor-bound protein 2 (GRB2), which drives IL-17 expression by an extracellular signal-regulated kinase-, IL-6- and STAT3-dependent mechanism. We showed that the IL-4Rα-R576 mutation elicits TH17 airway responses in vivo, in a house dust mite (HDM)- or ovalbumin (OVA)-driven model of airway inflammation in the mice carry the IL-4Rα-R576 mutation (Il4raR576 mice). Treg cell-specific deletion of genes encoding IL-6Rα or the master TH17 cell regulator Retinoid-related Orphan Receptor γt (RORγt), but not IL-4 and IL-13, protected mice against exacerbated airway inflammation induced by IL-4Rα--576. Analysis of lung tissue Treg cells revealed that the expression of IL-17 and the TH17 cell-associated chemokine receptor CCR6 was largely overlapping and highly enriched in Treg and conventional T (Tconv) cells of allergen-treated Il4raR576 mice. To further characterize the subset of IL-17 producing Foxp3+ Treg in the lung of OVA-treated mice we utilized CCR6 as a marker of Treg cells committed towards the TH17 cell lineage to examine their functional, epigenetic and transcriptional profiles. CCR6+Foxp3EGFP+ Treg cells isolated from OVA-sensitized and challenged Il4raR576 mice, by FACS (Fluorescence Activated Cell Sorting) exhibited decreased methylation of the Foxp3 CNS2 locus comparing to CCR6–Foxp3EGFP+ Treg cells from same animals, indicative of decreased stability. They also exhibited profoundly decreased suppressive function as compared to CCR6– WT and CCR6– Il4raR576 counterparts. Transcriptional profiling of CCR6+Foxp3EGFP+ Treg cells revealed increased relative expression in CCR6+ Il4raR576 Treg cells of genes associated with a TH17 cell signature, including Rorc, Ccr6, Il23r, Il17a, Il17f, Il1r1, Nr1d1, Cstl, and Ahr comparing to CCR6–Foxp3EGFP+ Treg cells from same animals.

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Low-dose allergen targeting to cDC2 induces long-term protection associated with IL-10+ Foxp3- CD8+ regulatory T cells in mice

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