Characterization of the function and co-expression patterns of human FOXP3 isoforms and their role in IPEX syndrome development. (P4146)

Abstract

Abstract IPEX syndrome is a rare and fatal X-linked recessive disorder due to mutations in the FOXP3 gene, which plays a critical role in the development and function of the regulatory T cells (Tregs) that maintain self-tolerance. Contrary to mice, humans possess three isoforms of FOXP3 with unknown function, and the expression of these isoforms is not restricted to Tregs. We determined the levels of expression and distribution of FOXP3 and other transcription factors isoforms in normal human T-cell subsets and in T cell subsets of patients with autoimmunity at the single-cell level by multiplex RT-qPCR and Flow cytometry and observed that expression of these isoforms is not restricted to Tregs, but can also be detected in naïve and activated/memory helper (Th) and in activated/memory CD8+ T cells. Distinct patterns of co-expression of the FOXP3 isoforms are modulated in response to inflammatory or autoimmune stimuli. Moreover, we observed that normal FOXP3 isoforms could induce bona fide regulatory function in Th cells. Our work supports the view that lack of FOXP3 expression in the effector T-cell populations in IPEX patients may contribute to the pathogenesis of the disease and suggests that FOXP3 deficiency can be corrected by gene transfer of the appropriate FOXP3 isoforms into conventional T-cells, which has important implication for the treatment of IPEX patients.