EBI3 ‐Dependent Pathways Coordinate Regulatory and Effector Immunity During Cutaneous Leishmaniasis

ABSTRACT Immunoregulatory pathways are critical for maintaining tissue homeostasis during Leishmania braziliensis infection; however, the mechanisms coordinating these responses remain poorly defined. Here, we investigated the role of Epstein–Barr virus‐induced gene 3 (EBI3), a shared subunit of IL‐27 and IL‐35, during cutaneous leishmaniasis. Human lesions showed increased expression of EBI3‐associated cytokine subunits, indicating activation of these pathways during infection. Using experimental models, we found that EBI3 deficiency exacerbated lesion development and parasite burden, whereas IL‐27 receptor deficiency did not. Loss of EBI3 selectively reduced Foxp3 + regulatory T cell populations and promoted excessive inflammatory responses, including neutrophil accumulation, altered macrophage responses, impaired inducible nitric oxide synthase expression and defective Th1‐associated immunity. Consequently, EBI3‐deficient mice failed to mount effective antiparasitic responses, leading to enhanced tissue pathology and parasite persistence. Together, our findings identify EBI3 as a central regulator of immune balance and protective immunity during L. braziliensis infection.