title: Toll-like receptor 9 and interferon-γ receptor signaling suppress the B-cell fate of uncommitted progenitors in mice.
abstract: Systemic inflammatory response syndrome describes a heterogeneous group of cytokine storm disorders, with different immunogens and cytokines leading to variations in organ pathology. The severe inflammation generated by the cytokine storm results in widespread organ pathology including alterations in T- and B-lymphocyte counts. This study explores the roles of TLR9 and IFN-γR stimulation in decreasing T- and B-cell lymphopoiesis in a mouse model of hyperinflammation. We demonstrate that early B-cell lymphopoiesis is severely compromised during TLR9- and IFN-γ-driven hyperinflammation from the Ly-6D(+) common lymphoid progenitor stage onwards with different effects inhibiting development at multiple stages. We show that TLR9 signaling directly decreases in vitro B-cell yields while increasing T-cell yields. IFN-γ also directly inhibits B-cell and T-cell differentiation in vitro as well as when induced by TLR9 in vivo. Microarray and RT-PCR analysis of Ly-6D(-) common lymphoid progenitors point to HOXa9 and EBF-1 as transcription factors altered by TLR9-induced inflammation. Our work demonstrates both cellular and molecular targets that lead to diminished B-cell lymphopoiesis in sustained TLR9- and IFN-γ-driven inflammation that may be relevant in a number of infectious and autoimmune/inflammatory settings.
authors: Division of Rheumatology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors: Sheena R
authors: SR
authors: Baratono
authors: Division of Rheumatology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors: Niansheng
authors: N
authors: Chu
authors: Division of Rheumatology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors: Lee P
authors: LP
authors: Richman
authors: Division of Rheumatology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors: Edward M
authors: EM
authors: Behrens
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D018899:CpG Islands / Q000276:immunology; D015536:Down-Regulation; D005260:Female; D058851:GPI-Linked Proteins / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D038041:Lymphopoiesis / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011828:Radiation Chimera; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism; D014158:Transcription, Genetic / Q000276:immunology
chemical_list: D000950:Antigens, Ly; D015815:Cell Adhesion Molecules; C489921:Ebf1 protein, mouse; D058851:GPI-Linked Proteins; D018398:Homeodomain Proteins; C094237:LY6D protein, human; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D015534:Trans-Activators; C097899:homeobox protein HOXA9; D007371:Interferon-gamma
keywords: B cells; Cytokines; Hematopoiesis; Inflammation; Transcription factors
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