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Identification of unstable regulatory and autoreactive effector T cells that are expanded in patients with FOXP3 mutations


Editor’s summary

The autoimmune disease immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX) is caused by mutations in FOXP3, the essential transcription factor for regulatory T cells (Tregs). Patients with IPEX have dysfunctional Tregs as well as an expansion of pathogenic autoreactive effector T cells. However, the source of these pathogenic cells is not clear. Here, Borna et al. characterized both the Treg and effector T cell populations of patients with IPEX compared with healthy controls or with patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED) caused by mutations in AIRE. The authors found that Tregs from patients with IPEX were uniquely unstable and that expanded autoreactive T cells partially originated from this unstable Treg pool. In addition to expressing autoimmunity-associated T cell receptors, the unstable Tregs acquired a TH2-skewed phenotype, which may further explain the quality of immune dysregulation observed in patients. These data further our understanding of the role of FOXP3 and how its mutation can drive autoimmunity. —Courtney Malo


Abstract

Studies of the monogenic autoimmune disease immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX) have elucidated the essential function of the transcription factor FOXP3 and thymic-derived regulatory T cells (Tregs) in controlling peripheral tolerance. However, the presence and the source of autoreactive T cells in IPEX remain undetermined. Here, we investigated how FOXP3 deficiency affects the T cell receptor (TCR) repertoire and Treg stability in vivo and compared T cell abnormalities in patients with IPEX with those in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED). To study Tregs independently of their phenotype and to analyze T cell autoreactivity, we combined Treg-specific demethylation region analyses, single-cell multiomic profiling, and bulk TCR sequencing. We found that patients with IPEX, unlike patients with APECED, have expanded autoreactive T cells originating from both autoreactive effector T cells (Teffs) and Tregs. In addition, a fraction of the expanded Tregs from patients with IPEX lost their phenotypic and functional markers, including CD25 and FOXP3. Functional experiments with CRISPR-Cas9–mediated FOXP3 knockout Tregs and Tregs from patients with IPEX indicated that the patients’ Tregs gain a TH2-skewed Teff-like function, which is consistent with immune dysregulation observed in these patients. Analyses of FOXP3 mutation-carrier mothers and a patient with IPEX after hematopoietic stem cell transplantation indicated that Tregs expressing nonmutated FOXP3 prevent the accumulation of autoreactive Teffs and unstable Tregs. These findings could be directly used for diagnostic and prognostic purposes and for monitoring the effects of immunomodulatory treatments.

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