Deletion of the exon 2 of mouse Foxp3 results in systemic lupus erythematosus-like disease

Abstract

Abstract Regulatory CD4 T cells (Tregs) are indispensable in maintaining self-tolerance and deficiency in Treg development and function leads to autoimmunity. Foxp3 is the master transcription factor determining Treg differentiation and function in both humans and mice. Unlike the mouse Foxp3 gene which only expresses a single product, human FOXP3 gene encodes at least two major isoforms (a full length and a short isoform lacking exon 2) through alternative splicing. The region of human FOXP3 encoded by exon2 binds to RORα and RORγt in vitro and regulates their transcription activity. However, how Foxp3 exon 2 regulates Treg development and function in vivo remains largely unknown. In order to understand the role of exon 2 in vivo, we deleted the exon 2 of mouse Foxp3 gene. Exon 2 knockout (dE2) mice showed splenomegaly/lymphadenopathy and produced higher ratio of Tfh and Tfr when compared with wildtype mice. Despite increased Treg compartment, dE2 mice generated autoreactive IgG against dsDNA and nuclear antigens. Histological examination of kidney revealed immune-complex deposits and glomerulonephritis. The dE2 mice also exhibited skin lesions on face, neck and back of the body starting 6 month after birth. Our data suggest that exon 2 of Foxp3 is critical in maintaining proper Treg function and self-tolerance.