Deficiency of T follicular helper cell <i>Tet3</i> DNA demethylation inhibits pathogenic IgG2c class switching and chronic GVHD
Abstract
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.
Article Details
Authors (19)
Michael C. Zaiken
1Division of Pediatric Blood and Marrow Transplantation & Cellular Therapy, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN
Sujeong Jin
1University of Minnesota, Division of Blood and Marrow Transplantation, Department of Pediatrics, Minneapolis, United States
Cameron S. McDonald-Hyman
1Division of Pediatric Blood and Marrow Transplantation & Cellular Therapy, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN
Christina R. Hartigan
1Division of Pediatric Blood and Marrow Transplantation & Cellular Therapy, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN
Peter T. Sage
Keli L. Hippen
1Division of Pediatric Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota Cancer Center, Minneapolis, MN
Brent H. Koehn
1Division of Pediatric Blood and Marrow Transplantation & Cellular Therapy, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN
Angela Panoskaltsis-Mortari
Megan J. Riddle
1Division of Pediatric Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota Cancer Center, Minneapolis, MN
Cindy R. Eide
1Division of Pediatric Blood and Marrow Transplantation & Cellular Therapy, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN
Jakub Tolar
1Division of Pediatric Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota Cancer Center, Minneapolis, MN
Geoffrey R. Hill
Leo Luznik
2Baylor College of Medicine, Medicine, Houston, United States
Corey S. Cutler
7Division of Hematologic Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
Jerome R. Ritz
17Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
Leslie S. Kean
Dana–Farber Cancer Institute–Boston Children’s Hospital, Boston
Ageliki Tsagaratou
11Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC
Anjana Rao
Bruce R. Blazar
Department of Pediatrics, Division of Blood & Marrow Transplant & Cellular Therapy, University of Minnesota