Deficiency of T follicular helper cell Tet3 DNA demethylation inhibits pathogenic IgG2c class switching and chronic GVHD

Authors

• Michael C Zaiken
• Sujeong Jin
• Cameron S McDonald-Hyman
• Christina R Hartigan
• Peter T Sage
• Keli L Hippen
• Brent H Koehn
• Angela Panoskaltsis-Mortari
• Megan J Riddle
• Cindy R Eide
• Jakub Tolar
• Geoffrey R Hill
• Leo Luznik
• Corey S Cutler
• Jerome R Ritz
• Leslie S Kean
• Ageliki Tsagaratou
• Anjana Rao
• Bruce R Blazar

Language

English

Publication Date

6-12-2025

Journal

Blood

DOI

10.1182/blood.2024025036

PMID

39899881

PMCID

PMC12226767

PubMedCentral® Posted Date

2-5-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Chronic graft-versus-host disease (cGVHD) is the leading cause of morbidity and nonrelapse-associated mortality after allogeneic hematopoietic cell transplantation. Treating steroid resistant/refractory cGVHD remains challenging. Epigenetic regulators can have global transcriptional effects that control donor T-cell responses. We previously showed that inhibiting histone lysine motifs by chromatin-modifying enzymes can ameliorate murine cGVHD. Targeting donor T-cell DNA methyltransferases reduce acute GVHD. In this study, we sought to investigate the DNA demethylase ten-eleven translocase (Tet) methylcytosine dioxygenases 2 (Tet2) and 3 (Tet3) in T follicular helper cell (TFH)-dependent cGVHD. In a clinically relevant model of cGVHD that recapitulates pulmonary fibrosis from bronchiolitis obliterans, recipients of Tet2-deleted donor T cells did not have improved pulmonary function tests in contrast with the markedly improved pulmonary function in Tet3-deleted donor T cells. Tet3 deleted donor T cells did not impair TFH-dependent germinal center (GC) formation. Unexpectedly, TET3 deficiency led to elevated GATA3 (GATA-binding protein 3) expression in and interleukin-4 production by TFHs. TET3-deficient TFHs supported GC B-cell immunoglobulin (Ig) class switching to nonpathogenic IgG1 but not pathogenic IgG2c, thereby enabling mice to escape cGVHD pulmonary fibrosis. Elevated GATA3 expression and disruption of IgG2c class switching was recapitulated in an in vitro human GC culture system. These studies provide new insights into the function of Tet3 in TFH-driven immunoglobulin class switching and suggest a new approach to mitigate cGVHD.

Keywords

Animals, Graft vs Host Disease, Dioxygenases, Mice, Immunoglobulin Class Switching, Chronic Disease, Proto-Oncogene Proteins, DNA Demethylation, T Follicular Helper Cells, DNA-Binding Proteins, Mice, Inbred C57BL, Mice, Knockout, T-Lymphocytes, Helper-Inducer, Immunoglobulin G

Published Open-Access

yes

Recommended Citation

Zaiken, Michael C; Jin, Sujeong; McDonald-Hyman, Cameron S; et al., "Deficiency of T follicular helper cell Tet3 DNA demethylation inhibits pathogenic IgG2c class switching and chronic GVHD" (2025). Faculty, Staff and Students Publications. 8135.
https://digitalcommons.library.tmc.edu/baylor_docs/8135