Clarification of human blood ILC subtype interrelatedness and discovery of amphiregulin production by human NK cells shed light on HIV-1 pathogenesis [preprint]
Authors
Wang, YetaoLifshitz, Lawrence M.
Silverstein, Noah J.
Mintzer, Esther
Luk, Kevin
St. Louis, Pamela
Brehm, Michael A.
Wolfe, Scot A.
Deeks, Steven G.
Luban, Jeremy
UMass Chan Affiliations
Graduate School of Biomedical SciencesDepartment of Biochemistry and Molecular Pharmacology
Diabetes Center of Excellence
Department of Molecular, Cell and Cancer Biology
Program in Molecular Medicine
Document Type
PreprintPublication Date
2021-06-08Keywords
ImmunologyHIV-1
cytokines
pathology
Amino Acids, Peptides, and Proteins
Animal Experimentation and Research
Immunology of Infectious Disease
Investigative Techniques
Nucleic Acids, Nucleotides, and Nucleosides
Pathology
Viruses
Metadata
Show full item recordAbstract
Human blood innate lymphoid cells (ILCs), which include ILCs and natural killer (NK) cells, derive from a common CD117+ILC precursor (ILCP). Yet, the relationship among the ILC subsets remains unclear. Bulk and single cell RNA-Seq and ATAC-Seq showed that blood ILC subsets cluster into ILC2s, ILCPs, a mixed cluster of CD56dim and CD56− NK cells, and a separate cluster of CD56hiNK cells that share features with both ILCs and CD56dimNK cells. In surprising contrast to mice, tissue repair protein amphiregulin was produced by human NK cells, with higher levels in CD56hiNK cells than in ILCs. Amphiregulin production by human NK cells was promoted by TCF7/WNT signaling and inhibited by TGFB1, a cytokine elevated in people living with HIV-1. Knockout of RUNX3, a WNT antagonist downstream of TGFB1, increased amphiregulin production in human NK cells. CD4+T cell depletion in people living with HIV-1, or from PBMCs in tissue culture, was associated with expansion of metabolically inert, nonfunctional CD56−NK cells. Experiments in tissue culture and in humanized mice revealed that CD56−NK cells are derived from CD56dimNK cells, and that CD4+T cell-derived IL-2 stimulates MTOR activity in CD56dimNK cells to prevent this transition. These findings clarify how ILC subsets are related to each other and provide insight into how HIV-1 infection disrupts ILC homeostasis and contributes to pathology.Source
bioRxiv 2021.04.20.440368; doi: https://doi.org/10.1101/2021.04.20.440368. Link to preprint on bioRxiv.
DOI
10.1101/2021.04.20.440368Permanent Link to this Item
http://hdl.handle.net/20.500.14038/29820Notes
This article is a preprint. Preprints are preliminary reports of work that have not been certified by peer review.
The PDF available for download is Version 2 of this preprint. The complete version history of this preprint is available at bioRxiv.
Rights
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.Distribution License
http://creativecommons.org/licenses/by-nc-nd/4.0/ae974a485f413a2113503eed53cd6c53
10.1101/2021.04.20.440368
Scopus Count
Except where otherwise noted, this item's license is described as The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.