Mechanism of Mitochondrial Transcription Factor A Attenuation of CpG-Induced Antibody Production.
Mitochondrial transcription factor A (TFAM) had previously been shown to act as a damage associated molecular pattern with the ability to enhance CpG-A phosphorothioate oligodeoxynucleotide (ODN)-mediated stimulation of IFNα production from human plasmacytoid dendritic cells. Examination of the mechanism by which TFAM might influence CpG ODN mediated innate immune responses revealed that TFAM binds directly, tightly and selectively to the structurally related CpG-A, -B, and -C ODN. TFAM also modulated the ability of the CpG-B or -C to stimulate the production of antibodies from human B cells. TFAM showed a dose-dependent modulation of CpG-B, and -C -induced antibody production from human B cells in vitro, with enhancement of high dose and inhibition of low doses of CpG stimulation. This effect was linked to the ability of TFAM to directly inhibit the binding of CpG ODNs to B cells, in a manner consistent with the relative binding affinities of TFAM for the ODNs. These data suggest that TFAM alters the free concentration of the CpG available to stimulate B cells by sequestering this ODN in a TFAM-CpG complex. Thus, TFAM has the potential to decrease the pathogenic consequences of exposure to natural CpG-like hypomethylated DNA in vivo, as well as such as that found in traumatic injury, infection, autoimmune disease and during pregnancy.
Department of Pharmacology and the Program in Structural Biology and Biochemistry, University of Colorado School of Medicine, Aurora, CO, 80045, United States of America.
Christopher S
CS
Malarkey
Mucosal and Vaccine Research Program Colorado (MAVRC), Department of Medicine and the Program in Immunology, University of Colorado School of Medicine, Aurora, CO, 80045, United States of America, and Denver Veterans Affairs Medical Center, Denver, CO, 80220, United States of America.
Claire E
CE
Gustafson
Department of Pharmacology and the Program in Structural Biology and Biochemistry, University of Colorado School of Medicine, Aurora, CO, 80045, United States of America.
Jessica F
JF
Saifee
Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, 80045, United States of America.
Raul M
RM
Torres
Department of Pharmacology and the Program in Structural Biology and Biochemistry, University of Colorado School of Medicine, Aurora, CO, 80045, United States of America.
Mair E A
http://orcid.org/0000-0003-0862-235X
ME
Churchill
Mucosal and Vaccine Research Program Colorado (MAVRC), Department of Medicine and the Program in Immunology, University of Colorado School of Medicine, Aurora, CO, 80045, United States of America, and Denver Veterans Affairs Medical Center, Denver, CO, 80220, United States of America.
Edward N
EN
Janoff
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000917:Antibody Formation; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects / Q000276:immunology*; D007074:Immunoglobulin G / Q000096:biosynthesis*; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D015398:Signal Transduction; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism
D000276:Adjuvants, Immunologic; C408982:CPG-oligonucleotide; D004268:DNA-Binding Proteins; D007074:Immunoglobulin G; D024101:Mitochondrial Proteins; D009838:Oligodeoxyribonucleotides; D014157:Transcription Factors; C422562:mitochondrial transcription factor A