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Fanconi anemia (FA) is a genetic disorder associated with bone marrow failure and leukemia. Recent studies demonstrate fundamental immune defects in FA. However, the mechanisms that are critical for FA immunodeficiency are not known. Here we report that deletion of Fancaor Fancd2dysregulates the suppressive activity of regulatory T cells (Tregs) and exacerbates graft-versus-host disease (GVHD) in mice.Recipient mice of Fanca-/-or Fancd2-/-bone marrow chimeras exhibited severe acute GVHD after allogeneic bone marrow transplantation (BMT). Further study showed that T cells from Fanca-/-or Fancd2-/-mice induced higher GVHD lethality than those from WT littermates. Mechanistically, FA Tregs possessed lower proliferative suppression potential compared to WT Tregs, as demonstrated by in vitroproliferation assay and BMT. Analysis of CD25+Foxp3+Tregs indicated that loss of Fancaor Fancd2dysregulated Foxp3 transcriptional activity. Additionally, CD25+Foxp3+Tregs of Fanca-/-or Fancd2-/-mice were less efficient in suppressing the production of GVHD-associated inflammatory cytokines. Consistently, incremental NF-kB transcriptional activity was observed in infiltrated T cells from FA GVHD mice. Conditional deletion of p65in FA Tregs desreased GVHD mortality. Our study uncovers an essential role for the FA proteins in maintaining Treg homeostasis and suggests that targeted blocking NF-kB signaling within T cells represents an attractive therapeutic strategy to ameliorate GVHD in FA.