Abstract
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.
Published Version
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