HIV-1 nef induces hck/lyn-dependent expansion of myeloid-derived suppressor cells associated with elevated interleukin-17/G-CSF levels
Por:
Priceputu E., Cool M., Bouchard N., Caceres-Cortes J.R., Lowell C.A., Hanna Z., Jolicoeur P.
Publicada:
1 ene 2021
Resumen:
Human immunodeficiency virus (HIV) or simian immunodeficiency virus (SIV) infection causes myelodysplasia, anemia, and accumulation of inflammatory monocytes (CD141 CD161) through largely unknown cellular and molecular pathways. The mouse cells thought to be equivalent to human CD141 CD161 cells are CD11b1 Gr11 myeloid-derived suppressor cells (MDSC). We used HIV transgenic (Tg) mouse models to study MDSC, namely, CD4C/Nef Tg mice expressing nef in dendritic cells (DC), pDC, CD41 T, and other mature and immature myeloid cells and CD11c/Nef Tg mice with a more restricted expression, mainly in DC and pDC. Both Tg strains showed expansion of granulocytic and CD11b1 Gr1low/int cells with MDSC characteristics. Fetal liver cell transplantation revealed that this expansion was stroma-independent and abrogated in mixed Tg/non-Tg 50% chimera. Tg bone marrow (BM) erythroid progenitors were decreased and myeloid precursors increased, suggesting an aberrant differentiation likely driving CD11b1 Gr11 cell expansion, apparently cell autonomously in CD4C/Nef Tg mice and likely through a bystander effect in CD11c/Nef Tg mice. Hck was activated in Tg spleen, and Nef-mediated CD11b1 Gr11 cell expansion was abrogated in Hck/Lyn-deficient Nef Tg mice, indicating a requirement of Hck/Lyn for this Nef function. IL-17 and granulocyte colony-stimulating factor (G-CSF) were elevated in Nef Tg mice. Increased G-CSF levels were normalized in Tg mice treated with anti-IL-17 antibodies. Therefore, Nef expression in myeloid precursors causes severe BM failure, apparently cell autonomously. More cell-restricted expression of Nef in DC and pDC appears sufficient to induce BM differentiation impairment, granulopoiesis, and expansion of MDSC at the expense of erythroid maturation, with IL-17!G-CSF as one likely bystander contributor. IMPORTANCE HIV-1 and SIV infection often lead to myelodysplasia, anemia, and accumulation of inflammatory monocytes (CD141 CD161), with the latter likely involved in neuroAIDS. We found that some transgenic (Tg) mouse models of AIDS also develop accumulation of mature and immature cells of the granulocytic lineage, decreased erythroid precursors, and expansion of MDSC (equivalent to human CD141 CD161 cells). We identified Nef as being responsible for these phenotypes, and its expression in mouse DC appears sufficient for their development through a bystander mechanism. Nef expression in myeloid progenitors may also favor myeloid cell expansion, likely in a cell-autonomous way. Hck/Lyn is required for the Nef-mediated accumulation of myeloid cells. Finally, we identified G-CSF under the control of IL-17 as one bystander mediator of MDSC expansion. Our findings provide a framework to determine whether the Nef.Hck/Lyn.IL-17.G-CSF pathway is involved in human AIDS and whether it represents a valid therapeutic target. Copyright © 2021 Priceputu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.
Filiaciones:
Priceputu E.:
Laboratory of Molecular Biology, Clinical Research Institute of Montreal, Montreal, QC, Canada
Cool M.:
Laboratory of Molecular Biology, Clinical Research Institute of Montreal, Montreal, QC, Canada
Bouchard N.:
Laboratory of Molecular Biology, Clinical Research Institute of Montreal, Montreal, QC, Canada
Caceres-Cortes J.R.:
Laboratory of Molecular Biology, Clinical Research Institute of Montreal, Montreal, QC, Canada
Lowell C.A.:
Department of Laboratory Medicine, University of California, San Francisco, CA, United States
Hanna Z.:
Laboratory of Molecular Biology, Clinical Research Institute of Montreal, Montreal, QC, Canada
Department of Medicine, University of Montréal, Montréal, QC, Canada
Division of Experimental Medicine, McGill University, Montreal, QC, Canada
Jolicoeur P.:
Laboratory of Molecular Biology, Clinical Research Institute of Montreal, Montreal, QC, Canada
Microbiology and Immunology, University of Montreal, Montreal, QC, Canada
Division of Experimental Medicine, McGill University, Montreal, QC, Canada
|