Single-cell analysis of normal and FOXP3-mutant human T cells: FOXP3 expression without regulatory T cell development

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Abstract
Forkhead winged-helix transcription factor Foxp3 serves as the dedicated mediator of the genetic program governing CD25+CD4+regulatory T cell (Tr) development and function in mice. In humans, its role in mediating Trdevelopment has been controversial. Furthermore, the fate of Trprecursors in FOXP3 deficiency has yet to be described. Making use of flow cytometric detection of human FOXP3, we have addressed the relationship between FOXP3 expression and human Trdevelopment. Unlike murine Foxp3−T cells, a small subset of human CD4+and CD8+T cells transiently up-regulated FOXP3 uponin vitrostimulation. Induced FOXP3, however, did not alter cell-surface phenotype or suppress T helper 1 cytokine expression. Furthermore, onlyex vivoFOXP3+Trcells persisted after prolonged culture, suggesting that induced FOXP3 did not activate a Trdevelopmental program in a significant number of cells. FOXP3 flow cytometry was also used to further characterize several patients exhibiting symptoms of immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) with or withoutFOXP3mutations. Most patients lacked FOXP3-expressing cells, further solidifying the association between FOXP3 deficiency and immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. Interestingly, one patient bearing aFOXP3mutation enabling expression of stable FOXP3mutprotein exhibited FOXP3mut-expressing cells among a subset of highly activated CD4+T cells. This observation raises the possibility that the severe autoimmunity in FOXP3 deficiency can be attributed, in part, to aggressive T helper cells that have developed from Trprecursors.