This study investigates the sex-specific heterogeneity of neutrophils and their role in the immunological outcome of auto-inflammatory Behçet’s uveitis (BU). Using single-cell RNA sequencing (scRNA-seq), the authors identified two unconventional neutrophil subsets—IFN-α-responsive and T cell regulatory—that exhibit dysregulation in male patients with BU. These subsets are associated with male-biased incidence, severity, and poor prognosis of the disease. The study also reveals that genetic factors and circulating exosomes negatively affect these unconventional neutrophil subsets, contributing to male-specific vulnerability to BU. Additionally, the authors found that IFN-α2a treatment can promote the differentiation of early/middle-phase neutrophil subsets to the T cell regulatory subset, enhancing their immune-regulatory function. In vivo experiments in a murine model of experimental autoimmune uveitis (EAU) further confirmed the regulatory role of T cell-regulatory neutrophils. The findings highlight the importance of sex-specific therapeutic targets, such as unconventional neutrophil subsets, in limiting inflammatory diseases.This study investigates the sex-specific heterogeneity of neutrophils and their role in the immunological outcome of auto-inflammatory Behçet’s uveitis (BU). Using single-cell RNA sequencing (scRNA-seq), the authors identified two unconventional neutrophil subsets—IFN-α-responsive and T cell regulatory—that exhibit dysregulation in male patients with BU. These subsets are associated with male-biased incidence, severity, and poor prognosis of the disease. The study also reveals that genetic factors and circulating exosomes negatively affect these unconventional neutrophil subsets, contributing to male-specific vulnerability to BU. Additionally, the authors found that IFN-α2a treatment can promote the differentiation of early/middle-phase neutrophil subsets to the T cell regulatory subset, enhancing their immune-regulatory function. In vivo experiments in a murine model of experimental autoimmune uveitis (EAU) further confirmed the regulatory role of T cell-regulatory neutrophils. The findings highlight the importance of sex-specific therapeutic targets, such as unconventional neutrophil subsets, in limiting inflammatory diseases.