Abstract
The transcription factor FOXP3 controls the immunosuppressive program in CD4+ T cells that is crucial for systemic immune regulation. Mutations of the single X-chromosomal FOXP3 gene in male individuals cause the inherited autoimmune disease immune dysregulation, polyendocrinopathy, enteropathy, and X-linked (IPEX) syndrome. Insufficient gene expression and impaired function of mutant FOXP3 protein prevent the generation of anti-inflammatory regulatory T (Treg) cells and fail to inhibit autoreactive T cell responses. Diversification of FOXP3 functional properties is achieved through alternative splicing that leads to isoforms lacking exon 2 (FOXP3Δ2), exon 7 (FOXP3Δ7), or both (FOXP3Δ2Δ7) specifically in human CD4+ T cells. Several IPEX mutations targeting these exons or promoting their alternative splicing revealed that those truncated isoforms cannot compensate for the loss of the full-length isoform (FOXP3fl). In this review, IPEX mutations that change the FOXP3 isoform profile and the resulting consequences for the CD4+ T-cell phenotype are discussed.
Highlights
Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare condition affecting less than one in a million newborns
IPEX syndrome is a monogenic disease caused by the mutation of the forkhead box P3 (FOXP3) gene, that encodes for the transcription factor FOXP3 [2, 3]
FOXP3 isoforms are co-expressed in CD4+ T cells but may differ in their respective ratio depending on T-cell antigen receptor (TCR) stimulation and cytokine activation
Summary
Polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare condition affecting less than one in a million newborns. Stimulation [41], whereas CD127 expression has been reported to increase in activated Treg cells in mice [42]. FOXP3 isoforms are co-expressed in CD4+ T cells but may differ in their respective ratio depending on TCR stimulation and cytokine activation.
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