Cytotoxic T-lymphocyte-associated protein 4-Ig effectively controls immune activation and inflammatory disease in a novel murine model of leaky severe combined immunodeficiency

Background: Severe combined immunodeficiency can be caused by loss-of-function mutations in genes involved in the DNA recombination machinery, such as recombination-activating gene 1 (RAG1), RAG2, orDNAcross-link repair 1C(DCLRE1C). Defective DNA recombination causes a developmental block in T and B cells, resulting in high susceptibility to infections. Hypomorphic mutations in the same genes can also give rise to a partial loss of T cells in a spectrum including leaky severe combined immunodeficiency (LS) and Omenn syndrome (OS). These patients not only experience life-threatening infections because of immunodeficiency but also experience inflammatory/autoimmune conditions caused by the presence of autoreactive T cells. Objective: We sought to develop a preclinical model that fully recapitulates the symptoms of patients with LS/OS, including a model for testing therapeutic intervention. Methods: We generated a novel mutant mouse (Dclre1c(leaky)) that develops a LS phenotype. Mice were monitored for diseases, and immune phenotype and immune function were evaluated by using flow cytometry, ELISA, and histology. Results: Dclre1c(leaky) mice present with a complete blockade of B-cell differentiation, with a leaky block in T-cell differentiation resulting in an oligoclonal T-cell receptor repertoire and enhanced cytokine secretion. Dclre1c(leaky) mice also had inflammatory symptoms, including wasting, dermatitis, colitis, hypereosinophilia, and high IgE levels. Development of a preclinical murine model for LS allowed testing of potential treatment, with administration of cytotoxic T-lymphocyteassociated protein 4-Ig reducing disease symptoms and immunologic disturbance, resulting in increased survival. Conclusion: These data suggest that cytotoxic T-lymphocyteassociated protein 4-Ig should be evaluated as a potential treatment of inflammatory symptoms in patients with LS and those with OS.