An Exon 2-deficient isoform of the Foxp3 gene fails to protect against IgE-mediated cutaneous autoimmunity after ultraviolet light exposure.

Abstract FOXP3 is required to maintain immune tolerance, but the functional contributions of FOXP3 isoforms to the maintenance of tolerance is poorly understood. Mice express a single isoform of the Foxp3 gene, but humans encode an additional exon 2-deficient splice variant isoform of FOXP3 with no known function. To determine how exon 2 of FOXP3 contributes to Treg activity, we generated mice that only express the exon 2-deficient FoxP3 variant (called B6.FoxP3ΔExon2). In the steady-state, B6.FoxP3ΔExon2 mice develop mild autoimmunity (splenomegaly, autoantibodies and kidney nephritis) with enlarged germinal centers and elevated titers of skin-reactive IgE. We also observed skin-reactive IgE antibodies in SLE patients with active photosensivity. Therefore, We challenged B6 and B6.FoxP3ΔExon2 mouse skin with ultraviolet B (UVB) light to determine if UVB damage can increase the production of self-reactive IgE. When compared to B6 controls, B6.FoxP3ΔExon2 mice developed greater skin inflammation with increased infiltration of IgE+ plasma cells (B220lowCD138+Blimp1 +) at the site of UVB damage. B6.FoxP3ΔExon2 mice also had higher numbers of IL4-producing T effector cells (IL4+CD4+CD44+Foxp3−) and IgE-producing B cells in draining lymph nodes of UVB-challenged skin as compared to untreated control lymph nodes. Finally, UVB-treated B6.FoxP3ΔExon2 mice also had worsened kidney nephritis and proteinurea, phenocopying multi-systemic flares that occur in SLE patients with photosensitivity. Collectively, we found that exon 2 of the Foxp3 gene is required to control cutaneous inflammation though the regulation of skin-reactive IgE, and IgE-producing B cells could be targeted to limit the severity of SLE-associated photosensitivity.