TY - JOUR
T1 - Identification of unstable regulatory and autoreactive effector T cells that are expanded in patients with FOXP3 mutations
AU - Borna, Šimon
AU - Lee, Esmond
AU - Nideffer, Jason
AU - Ramachandran, Akshaya
AU - Wang, Bing
AU - Baker, Jeanette
AU - Mavers, Melissa
AU - Lakshmanan, Uma
AU - Narula, Mansi
AU - Garrett, Amy Kang Hee
AU - Schulze, Janika
AU - Olek, Sven
AU - Marois, Louis
AU - Gernez, Yael
AU - Bhatia, Monica
AU - Chong, Hey Jin
AU - Walter, Jolan
AU - Kitcharoensakkul, Maleewan
AU - Lang, Abigail
AU - Cooper, Megan A.
AU - Bertaina, Alice
AU - Roncarolo, Maria Grazia
AU - Meffre, Eric
AU - Bacchetta, Rosa
N1 - Publisher Copyright:
© 2023 American Association for the Advancement of Science. All rights reserved.
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85177574395&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.adg6822
DO - 10.1126/scitranslmed.adg6822
M3 - Article
C2 - 38117899
AN - SCOPUS:85177574395
SN - 1946-6234
VL - 15
JO - Science translational medicine
JF - Science translational medicine
IS - 727
M1 - eadg6822
ER -