Regulatory T (Treg) cells play a central role in maintaining immune system homeostasis and modulating immune responses. Foxp3 is a master regulator of Treg development and function. FOXP3 mutations in patients with IPEX, which result in a deficiency in Tregs, result in lethal autoimmunity, similar to the disease observed in Foxp3 deficient mice. While highly conserved in both amino acid sequence and gene structure, one difference between humans and mice is that the human FOXP3 gene encodes two major alternatively spliced isoforms: a full length version that uses all 10 exons (FOXP3-FL, the only isoform in mice) and a shorter isoform lacking sequences shown to be important in regulating Th17 differentiation. Recent studies have shown that Tregs from patients with some autoimmune diseases express increased levels of the ?E2 isoform compared to those from healthy donors. Consistent with this finding, we have found that Tregs from SLE patients have increased expression of the FOXP3?Ex2 isoform. To study the role of the ?E2 isoform in Treg function we generated a new mouse strain with Foxp3 exon 2 deletion. Interestingly, we found that Foxp3?E2 mice develop hallmark features of SLE, including anti- DNA and anti-nuclear autoantibodies, increased number and size of spontaneous germinal centers and kidney deposition of antibody complexes, by 4-5 weeks of age. However, these mice do not develop full-blown disease and have a normal life span. Our central hypothesis is that the region encoded by exon 2 of Foxp3 gene is critical for normal Treg identity and function. To test this hypothesis we will take 2 approaches. First, we will determine the levels of FOXP3-FL and -?Ex2-expressing Tregs in healthy human subjects and subjects with autoimmune disease. These studies will be complemented with studies using mice containing varying ratios of Tregs expressing each isoform. Second, we test the hypothesis that Tregs expressing FOXP3-?Ex2 have a reduced ability to regulate effector T cell activation, using both human Treg clones and a mouse transfer colitis model. Together these studies will allow us to gain important information on the expression of FOXP3?Ex2 and the function of Tregs expressing this isoform.
Regulatory T cells (Tregs) are a specialized subset of T cells, regulated by the transcription factor FOXP3, that control peripheral tolerance. We have found that a FOXP3 isoform lacking sequences in exon 2 (FOXP3?Ex2) is increased in patients with immune-mediated diseases. To understand the role of cells expressing this isoform we have generated an animal model lacking this exon of Foxp3.
