VCAM1-expressing T cells and systemic autoimmunity in Regnase-1 deficiency

Autoimmunity develops as a result of a breakdown in immune tolerance and activation of autoreactive immune cells. Most of the common autoimmune diseases are polygenic1 suggesting dysregulation in multiple signalling pathways. By contrast, in monogenic Inborn Errors of Immunity (IEI), which also can result in autoimmunity, the disease is triggered by a single genetic defect. Therefore, the discovery of causative mutations in IEI allows tracing the molecular mechanisms leading to autoimmunity in humans from a defect in the function of a specific gene to patients clinical and immunological phenotype. Here, we discovered an IEI patient with systemic autoimmunity caused by a private homozygous protein-truncating mutation in gene ZC3H12A leading to deficiency of Regnase-1, a regulatory RNase2-5. Flow cytometry, bulk T cell transcriptome analysis and single-cell RNA sequencing demonstrated expansion of {gamma}{delta} T cells expressing VCAM-1 and IFN{gamma} genes. We show that Regnase-1 directly targets 3UTR of VCAM1 and the coding sequence of IFNG mRNAs. These findings highlight a new autoimmunity mechanism in humans, where Regnase-1 deficiency causes expansion of VCAM1+IFNG+ T cells and their interaction with integrin 4{beta}1-expressing B cells, which showed upregulation of IFN-response genes and activation, leading to systemic autoimmunity. Furthermore, we show that VCAM1+ T cells are present in organs of donors and are expanded in the blood of patients with systemic lupus erythematosus, a common autoimmune disease characterised by systemic autoimmunity.