title: Deletion of Fanca or Fancd2 dysregulates Treg in mice.
abstract: Fanconi anemia (FA) is a genetic disorder associated with bone marrow (BM) failure and leukemia. Recent studies demonstrate variable immune defects in FA. However, the cause for FA immunodeficiency is unknown. Here we report that deletion of Fanca or Fancd2 dysregulates the suppressive activity of regulatory T cells (Tregs), shown functionally as exacerbation of graft-vs-host disease (GVHD) in mice. Recipient mice of Fanca(-/-) or Fancd2(-/-) BM chimeras exhibited severe acute GVHD after allogeneic BM transplantation (BMT). T cells from Fanca(-/-) or Fancd2(-/-) mice induced higher GVHD lethality than those from wild-type (WT) littermates. FA Tregs possessed lower proliferative suppression potential compared with WT Tregs, as demonstrated by in vitro proliferation assay and BMT. Analysis of CD25(+)Foxp3(+) Tregs indicated that loss of Fanca or Fancd2 dysregulated Foxp3 target gene expression. Additionally, CD25(+)Foxp3(+) Tregs of Fanca(-/-) or Fancd2(-/-) mice were less efficient in suppressing the production of GVHD-associated inflammatory cytokines. Consistently, aberrant NF-κB activity was observed in infiltrated T cells from FA GVHD mice. Conditional deletion of p65 in FA Tregs decreased GVHD mortality. Our study uncovers an essential role for FA proteins in maintaining Treg homeostasis, possibly explaining, at least in part, the immune deficiency reported in some FA patients.
authors: Division of Experimental Hematology and Cancer Biology.
authors: Wei
authors: W
authors: Du
authors: Ozlem
authors: O
authors: Erden
authors: Andrew
authors: A
authors: Wilson
authors: Jared M
authors: JM
authors: Sipple
authors: Jonathan
authors: J
authors: Schick
authors: Parinda
authors: P
authors: Mehta
authors: Kasiani C
authors: KC
authors: Myers
authors: Kris A
authors: KA
authors: Steinbrecher
authors: Stella M
authors: SM
authors: Davies
authors: Qishen
authors: Q
authors: Pang
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D016207:Cytokines / Q000096:biosynthesis; D005199:Fanconi Anemia / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D052217:Fanconi Anemia Complementation Group A Protein / Q000172:deficiency* / Q000235:genetics / Q000276:immunology*; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000172:deficiency* / Q000235:genetics / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000378:metabolism; D015870:Gene Expression; D006086:Graft vs Host Disease / Q000276:immunology / Q000473:pathology; D006801:Humans; D007108:Immune Tolerance; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D018183:Transplantation Chimera
chemical_list: D016207:Cytokines; C120277:Fanca protein, mouse; C499904:Fancd2 protein, mouse; D052217:Fanconi Anemia Complementation Group A Protein; D052236:Fanconi Anemia Complementation Group D2 Protein; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse