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

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 in an Ovalbumin (OVA)-mediated allergy mouse model whether direct allergen targeting to DC subsets can induce desensitization. A Standard desensitization protocol was compared with an antibody-OVA fusion protein targeting the conventional cDC1 or cDC2 subsets via their respective receptors CD205 (CD205-Fp) or DCIR2 (DCIR2-Fp). Allergen targeting to cDC2 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 (Foxp3+ Treg). DCIR2-Fp therapy initially expanded IL-10+ and IL-10- Foxp3+ Treg, but these levels returned to baseline. On day 80, we identified Foxp3- CD44high Treg-like CD8+ as the primary source of IL-10. Overall, our data suggest that cDC2 allergen targeting in allergic mice offers a potent, long-lasting IL-10-dependent desensitizing effect.