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

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.