Title

Clarification of human blood ILC subtype interrelatedness and discovery of amphiregulin production by human NK cells shed light on HIV-1 pathogenesis [preprint]

Authors

Yetao Wang, University of Massachusetts Medical SchoolFollow
Lawrence M. Lifshitz, University of Massachusetts Medical SchoolFollow
Noah J. Silverstein, University of Massachusetts Medical SchoolFollow
Esther Mintzer, University of Massachusetts Medical SchoolFollow
Kevin Luk, University of Massachusetts Medical SchoolFollow
Pamela St. Louis, University of Massachusetts Medical SchoolFollow
Michael A. Brehm, University of Massachusetts Medical SchoolFollow
Scot A. Wolfe, University of Massachusetts Medical SchoolFollow
Steven G. Deeks, University of California, San Francisco
Jeremy Luban, University of Massachusetts Medical SchoolFollow

UMMS Affiliation

Program in Molecular Medicine; Department of Molecular, Cell and Cancer Biology; Diabetes Center of Excellence; Department of Biochemistry and Molecular Pharmacology; Graduate School of Biomedical Sciences

Publication Date

2021-06-08

Document Type

Article Preprint

Disciplines

Amino Acids, Peptides, and Proteins | Animal Experimentation and Research | Immunology of Infectious Disease | Investigative Techniques | Nucleic Acids, Nucleotides, and Nucleosides | Pathology | Viruses

Abstract

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 CD56^dim and CD56⁻ NK cells, and a separate cluster of CD56^hiNK cells that share features with both ILCs and CD56^dimNK cells. In surprising contrast to mice, tissue repair protein amphiregulin was produced by human NK cells, with higher levels in CD56^hiNK 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 CD56^dimNK cells, and that CD4⁺T cell-derived IL-2 stimulates MTOR activity in CD56^dimNK 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.

Keywords

Immunology, HIV-1, cytokines, pathology

Rights and Permissions

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.

DOI of Published Version

10.1101/2021.04.20.440368

Source

bioRxiv 2021.04.20.440368; doi: https://doi.org/10.1101/2021.04.20.440368. Link to preprint on bioRxiv.

Comments

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.

Journal/Book/Conference Title

bioRxiv

Repository Citation

Wang Y, Lifshitz LM, Silverstein NJ, Mintzer E, Luk K, St. Louis P, Brehm MA, Wolfe SA, Deeks SG, Luban J. (2021). Clarification of human blood ILC subtype interrelatedness and discovery of amphiregulin production by human NK cells shed light on HIV-1 pathogenesis [preprint]. UMass Chan Medical School Faculty Publications. https://doi.org/10.1101/2021.04.20.440368. Retrieved from https://escholarship.umassmed.edu/faculty_pubs/2028

Creative Commons License

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.