Frontiers in immunology · 2026
Loss of TET function in T regulatory cells yields ex-Treg cells biased toward T follicular helper cells, causing autoimmune diseases through autoantibody production.
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Suzuki Kazumasa, Arteaga-Vazquez Leo J, Villalobos Reveles Bruno, Hernández-Espinosa Lot, López-Moyado Isaac F, Onodera Atsushi, Samaniego-Castruita Daniela, Ay Ferhat, Lara-Custodio Arlet, Hogan Patrick G, Sepulveda Hugo, Rao Anjana
Аннотация
INTRODUCTION: T regulatory cells (Treg cells) express the transcription factor FOXP3 and maintain immune homeostasis by attenuating effector responses. Treg cells are prone to lose FOXP3 and convert to pathological 'ex-Treg' cells under conditions of strong or chronic inflammation. One mechanism for loss of FOXP3 expression involves increased DNA methylation of intronic enhancers CNS1 and CNS2 in the Foxp3 locus; these enhancers are maintained in a demethylated state by TET enzymes, 5-methylcytosine (5mC) dioxygenases that generate 5-hydroxymethylcytosine (5hmC) and other oxidized methylcytosines that are essential intermediates in all pathways of DNA demethylation. We previously showed that FOXP3+ Treg cells from Tet2/3-deficient (Tet2/3 DKO) mice displayed increased methylation of CNS1 and CNS2 and converted to FOXP3-negative ex-Treg cells considerably more efficiently than wild-type (WT) Treg cells.
METHOD: We extend our previous analysis of Foxp3-Cre Tet2/3 fl/fl mice.
RESULTS AND DISCUSSION: We classified the mice as DKO-moderate or DKO-severe based on the total number of leukocytes in the spleen and peripheral lymph nodes and investigated the phenotypic and molecular basis for the progressive inflammation occurring in these mice. RNA-seq as well as histological and immunocytochemical analyses showed a striking expansion of T follicular helper (Tfh) cells and plasma cells in Tet2/3 DKO-severe mice. And single-cell (sc) RNA-seq analyses suggested that this was due to skewed differentiation of both Tet2/3 DKO FOXP3+ Treg cells and Tet2/3 DKO FOXP3 - ex-Treg cells into Tfh-like cells. Base-resolution "6-base" sequencing showed the expected loss of 5hmC and increased 5mC in Tfh cells purified from Tet2/3 DKO-severe mice, and suggested that the observed bias in gene expression patterns could arise either from a direct increase in methylation of essential enhancers due to TET deficiency, or from interference with binding of methylation-sensitive transcriptional repressors including CCCTC-bindingfactor (CTCF).
METHOD: We extend our previous analysis of Foxp3-Cre Tet2/3 fl/fl mice.
RESULTS AND DISCUSSION: We classified the mice as DKO-moderate or DKO-severe based on the total number of leukocytes in the spleen and peripheral lymph nodes and investigated the phenotypic and molecular basis for the progressive inflammation occurring in these mice. RNA-seq as well as histological and immunocytochemical analyses showed a striking expansion of T follicular helper (Tfh) cells and plasma cells in Tet2/3 DKO-severe mice. And single-cell (sc) RNA-seq analyses suggested that this was due to skewed differentiation of both Tet2/3 DKO FOXP3+ Treg cells and Tet2/3 DKO FOXP3 - ex-Treg cells into Tfh-like cells. Base-resolution "6-base" sequencing showed the expected loss of 5hmC and increased 5mC in Tfh cells purified from Tet2/3 DKO-severe mice, and suggested that the observed bias in gene expression patterns could arise either from a direct increase in methylation of essential enhancers due to TET deficiency, or from interference with binding of methylation-sensitive transcriptional repressors including CCCTC-bindingfactor (CTCF).