The Role of IFNγ‐Producing Th1 Cells in a Type I IFN‐Independent Murine Model of Autoinflammation Resulting from DNase II‐Deficiency

OBJECTIVE: Patients with hypomorphic mutations in DNase II develop a severe and debilitating autoinflammatory disease. This study was undertaken to compare the disease parameters in these patients to those in a murine model of DNase II deficiency, and to evaluate the role of specific nucleic acid sensors and identify the cell types responsible for driving the autoinflammatory response. METHODS: To avoid embryonic death, Dnase2(-/-) mice were intercrossed with mice that lacked the type I interferon (IFN) receptor (Ifnar(-/-) ). The hematologic changes and immune status of these mice were evaluated using complete blood cell counts, flow cytometry, serum cytokine enzyme-linked immunosorbent assays, and liver histology. Effector cell activity was determined by transferring T cells from Dnase2(-/-) x Ifnar(-/-) double-knockout (DKO) mice into Rag1(-/-) mice, and 4 weeks after cell transfer, induced changes were assessed in the recipient mice. RESULTS: In Dnase2(-/-) x Ifnar(-/-) DKO mice, many of the disease features found in DNase II-deficient patients were recapitulated, including cytopenia, extramedullary hematopoiesis, and liver fibrosis. Dnase2(+/+) x Rag1(-/-) mice (n > 22) developed a hematologic disorder that was attributed to the transfer of an unusual IFNgamma-producing T cell subset from the spleens of donor Dnase2(-/-) x Ifnar(-/-) DKO mice. Autoinflammation in this murine model did not depend on the stimulator of IFN genes (STING) pathway but was highly dependent on the chaperone protein Unc93B1. CONCLUSION: Dnase2(-/-) x Ifnar(-/-) DKO mice may be a valid model for exploring the innate and adaptive immune mechanisms responsible for the autoinflammation similar to that seen in DNASE2-hypomorphic patients. In this murine model, IFNgamma is required for T cell activation and the development of clinical manifestations. The role of IFNgamma in DNASE2-deficient patient populations remains to be determined, but the ability of Dnase2(-/-) mouse T cells to transfer disease to Rag1(-/-) mice suggests that T cells may be a relevant therapeutic target in patients with IFN-related systemic autoinflammatory diseases.