Toll-like receptor 7-adapter complex modulates interferon-α production in HIV-stimulated plasmacytoid dendritic cells
Autoři:
Andy A. Patamawenu aff001; Nathaniel E. Wright aff001; Tulley Shofner aff001; Sean Evans aff001; Maura M. Manion aff001; Nicole Doria-Rose aff001; Stephen A. Migueles aff001; Daniel Mendoza aff001; Bennett Peterson aff001; Christopher Wilhelm aff001; Julia Rood aff001; Amy Berkley aff001; Nancy A. Cogliano aff001; C. Jason Liang aff002; Kiki Tesselaar aff003; Frank Miedema aff003; Julian Bess, Jr. aff004; Jeffrey Lifson aff004; Mark Connors aff001
Působiště autorů:
HIV-Specific Immunity Section of the Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
aff001; Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
aff002; Department of Immunology, University Medical Center Utrecht, Utrecht, Netherlands
aff003; AIDS and Cancer Virus Program, Frederick National Laboratory, Frederick, Maryland, United States of America
aff004
Vyšlo v časopise:
PLoS ONE 14(12)
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pone.0225806
Souhrn
Plasmacytoid dendritic cells (PDCs) and their production of interferon-alpha (IFN-α) are believed to play an important role in human immunodeficiency virus, type I (HIV-1) pathogenesis. PDCs produce IFN-α and other proinflammatory cytokines through stimulation of Toll-like receptor 7 (TLR7) and TLR9 present in endosomal compartments. TLR7 recognizes single-stranded viral RNA, while TLR9 recognizes unmethylated DNA. In this study, we examined the mechanisms that may underlie variations in IFN-α production in response to HIV, and the impact of these variations on HIV pathogenesis. In four distinct cohorts, we examined PDC production of IFN-α upon stimulation with inactivated HIV-1 particles and unmethylated DNA. The signaling cascade of TLR7 bifurcates at the myeloid differentiation protein 88 (MyD88) adaptor protein to induce expression of either IFN-α or TNF-α. To determine whether variations in IFN-α production are modulated at the level of the receptor complex or downstream of it, we correlated production of IFN-α and TNF-α following stimulation of TLR7 or TLR9 receptors. Flow cytometry detection of intracellular cytokines showed strong, direct correlations between IFN-α and TNF-α expression in all four cohorts, suggesting that variations in IFN-α production are not due to variations downstream of the receptor complex. We then investigated the events upstream of TLR binding by using lipid-like vesicles to deliver TLR ligands directly to the TLR receptors, bypassing the need for CD4 binding and endocytosis. Similar tight correlations were found in IFN-α and TNF-α production in response to the TLR ligands. Taken together, these results strongly suggest that differences in IFN-α production depend on the regulatory processes at the level of the TLR7 receptor complex. Additionally, we found no association between IFN-α production before HIV infection and disease progression.
Klíčová slova:
Cytokines – Flow cytometry – HIV-1 – Immune receptor signaling – Men who have sex with men – T cells – Toll-like receptors
Zdroje
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Článek vyšel v časopise
PLOS One
2019 Číslo 12
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