title: IFN regulatory factor 8 represses GM-CSF expression in T cells to affect myeloid cell lineage differentiation.
abstract: During hematopoiesis, hematopoietic stem cells constantly differentiate into granulocytes and macrophages via a distinct differentiation program that is tightly controlled by myeloid lineage-specific transcription factors. Mice with a null mutation of IFN regulatory factor 8 (IRF8) accumulate CD11b(+)Gr1(+) myeloid cells that phenotypically and functionally resemble tumor-induced myeloid-derived suppressor cells (MDSCs), indicating an essential role of IRF8 in myeloid cell lineage differentiation. However, IRF8 is expressed in various types of immune cells, and whether IRF8 functions intrinsically or extrinsically in regulation of myeloid cell lineage differentiation is not fully understood. In this study, we report an intriguing finding that, although IRF8-deficient mice exhibit deregulated myeloid cell differentiation and resultant accumulation of CD11b(+)Gr1(+) MDSCs, surprisingly, mice with IRF8 deficiency only in myeloid cells exhibit no abnormal myeloid cell lineage differentiation. Instead, mice with IRF8 deficiency only in T cells exhibited deregulated myeloid cell differentiation and MDSC accumulation. We further demonstrated that IRF8-deficient T cells exhibit elevated GM-CSF expression and secretion. Treatment of mice with GM-CSF increased MDSC accumulation, and adoptive transfer of IRF8-deficient T cells, but not GM-CSF-deficient T cells, increased MDSC accumulation in the recipient chimeric mice. Moreover, overexpression of IRF8 decreased GM-CSF expression in T cells. Our data determine that, in addition to its intrinsic function as an apoptosis regulator in myeloid cells, IRF8 also acts extrinsically to repress GM-CSF expression in T cells to control myeloid cell lineage differentiation, revealing a novel mechanism that the adaptive immune component of the immune system regulates the innate immune cell myelopoiesis in vivo.
authors: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912; Cancer Immunology, Inflammation and Tolerance Program, Cancer Center, Georgia Regents University, Augusta, GA 30912; Charlie Norwood VA Medical Center, Augusta, GA 30904;
authors: Amy V
authors: AV
authors: Paschall
authors: Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors: Ruihua
authors: R
authors: Zhang
authors: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
authors: Chen-Feng
authors: CF
authors: Qi
authors: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912;
authors: Kankana
authors: K
authors: Bardhan
authors: Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors: Liang
authors: L
authors: Peng
authors: Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors: Geming
authors: G
authors: Lu
authors: Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors: Jianjun
authors: J
authors: Yang
authors: Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors: Miriam
authors: M
authors: Merad
authors: Cancer Immunology, Inflammation and Tolerance Program, Cancer Center, Georgia Regents University, Augusta, GA 30912;
authors: Tracy
authors: T
authors: McGaha
authors: Cancer Immunology, Inflammation and Tolerance Program, Cancer Center, Georgia Regents University, Augusta, GA 30912;
authors: Gang
authors: G
authors: Zhou
authors: Cancer Immunology, Inflammation and Tolerance Program, Cancer Center, Georgia Regents University, Augusta, GA 30912;
authors: Andrew
authors: A
authors: Mellor
authors: Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263; and.
authors: Scott I
authors: SI
authors: Abrams
authors: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
authors: Herbert C
authors: HC
authors: Morse
authors: Programs in Genomics of Differentiation, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892.
authors: Keiko
authors: K
authors: Ozato
authors: Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029; huabao.xiong@mssm.edu kliu@gru.edu.
authors: Huabao
authors: H
authors: Xiong
authors: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912; Cancer Immunology, Inflammation and Tolerance Program, Cancer Center, Georgia Regents University, Augusta, GA 30912; Charlie Norwood VA Medical Center, Augusta, GA 30904; huabao.xiong@mssm.edu kliu@gru.edu.
authors: Kebin
authors: K
authors: Liu
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D039481:CD11b Antigen / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D019070:Cell Lineage / Q000235:genetics / Q000276:immunology*; D049109:Cell Proliferation; D002678:Chimera; D005786:Gene Expression Regulation; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D050835:Interferon Regulatory Factors / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D051379:Mice; D022423:Myeloid Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D038042:Myelopoiesis / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000637:transplantation; D000099185:Interferon Regulatory Factor-8
chemical_list: D039481:CD11b Antigen; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D050835:Interferon Regulatory Factors; D000099185:Interferon Regulatory Factor-8
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