Janus Kinase Inhibitor Treatment Results in Rapid but Incomplete Immune Reconstitution and Resolution of Monocyte-Driven Hyperinflammation in STAT1 Gain-of-Function

Autosomal-dominant STAT1 gain-of-function (GOF) is an inborn error of immunity characterized by chronic mucocutaneous candidiasis and variable autoimmune manifestations. Janus kinase (JAK) inhibitors are a promising treatment, but their efficacy remains variable and incompletely understood. We evaluated the impact of JAK inhibitors by studying two STAT1 GOF patients (harboring R321S and T385M mutations) longitudinally using Cellular Indexing of Transcriptomes and Epitopes by sequencing (CITE-seq), flow cytometry, and cytokine analysis in peripheral blood mononuclear cells and serum. Rapid, yet incomplete, immune reconstitution was observed after 1 week. T cells rebalanced from effector to naïve T cells, and T cell receptor diversity and abundance increased. Monocytes showed the most pronounced transcriptional dysregulation compared to healthy references, which markedly improved upon JAK-inhibitor treatment. Serum cytokine, cell–cell communication, and pathway analysis pointed toward an inflammatory phenotype in all cell types caused by monocytes and improved upon treatment. JAK inhibitors provided clinical and immunological benefit in STAT1 GOF but did not fully restore immune homeostasis, highlighting both its therapeutic potential and limitations.