PMID- 34752140 OWN - NLM STAT- MEDLINE DCOM- 20220117 LR - 20220510 IS - 1937-9145 (Electronic) IS - 1945-0877 (Print) IS - 1945-0877 (Linking) VI - 14 IP - 708 DP - 2021 Nov 9 TI - Dynamic variability in SHP-1 abundance determines natural killer cell responsiveness. PG - eabe5380 LID - 10.1126/scisignal.abe5380 [doi] AB - Interactions between human leukocyte antigen (HLA) molecules on target cells and the inhibitory killer cell immunoglobulin-like receptors (KIRs) and heterodimeric inhibitory receptor CD94-NKG2A on human natural killer (NK) cells shape and program various response capacities. A functionally orthologous system exists in mice, consisting of major histocompatibility complex (MHC) molecules on target cells and the inhibitory Ly49 and CD94-NKG2A receptors on NK cells. Here, we found that the abundance of Src homology 2 domain-containing phosphatase-1 (SHP-1) in NK cells was established by interactions between MHCs and NK cell inhibitory receptors, although phenotypically identical NK cell populations still showed substantial variability in endogenous SHP-1 abundance and NK cell response potential. Human and mouse NK cell populations with high responsiveness had low SHP-1 abundance, and a reduction in SHP-1 abundance in NK cells enhanced their responsiveness. Computational modeling of NK cell activation by membrane-proximal signaling events identified SHP-1 as a negative amplitude regulator, which was validated by single-cell analysis of human NK cell responsiveness. The amount of mRNA and protein varied among responsive NK cells despite their similar chromatin accessibility to that of unresponsive cells, suggesting dynamic regulation of SHP-1 abundance. Low intracellular SHP-1 abundance was a biomarker of responsive NK cells. Together, these data suggest that enhancing NK cell function through the acute loss of SHP-1 abundance or activity may enhance the tumoricidal capacity of NK cells. FAU - Wu, Zeguang AU - Wu Z AUID- ORCID: 0000-0001-9988-4173 AD - Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. AD - Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. FAU - Park, Soo AU - Park S AD - Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. AD - Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. FAU - Lau, Colleen M AU - Lau CM AUID- ORCID: 0000-0001-7538-094X AD - Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. FAU - Zhong, Yi AU - Zhong Y AD - Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. FAU - Sheppard, Sam AU - Sheppard S AD - Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. FAU - Sun, Joseph C AU - Sun JC AUID- ORCID: 0000-0001-8062-9033 AD - Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. AD - Department of Immunology and Microbial Pathogenesis, Weill Cornell Medical College, New York, NY 10065, USA. AD - Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. FAU - Das, Jayajit AU - Das J AUID- ORCID: 0000-0001-9649-4698 AD - Battelle Center for Mathematical Medicine, Research Institute at the Nationwide Children's Hospital, Columbus, OH 43205, USA. AD - Department of Pediatrics, Pelotonia Institute of ImmunoOncology, Wexner College of Medicine, Ohio State University, Columbus, OH 43210, USA. AD - Department of Biomedical Informatics, Ohio State University, Columbus, OH 43210, USA. AD - Biophysics Graduate Program, Ohio State University, Columbus, OH 43210, USA. FAU - Altan-Bonnet, Gregoire AU - Altan-Bonnet G AUID- ORCID: 0000-0002-7283-3162 AD - Immunodynamics Group, Cancer and Inflammation Program, National Cancer Institute, National Institutes of Health, Bethesda, MD 20814, USA. FAU - Hsu, Katharine C AU - Hsu KC AUID- ORCID: 0000-0003-2827-5324 AD - Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. AD - Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. AD - Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. AD - Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA. AD - Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. LA - eng GR - R01 AI125651/AI/NIAID NIH HHS/United States GR - R01 AI100874/AI/NIAID NIH HHS/United States GR - P01 CA023766/CA/NCI NIH HHS/United States GR - P30 CA008748/CA/NCI NIH HHS/United States GR - R01 AI146581/AI/NIAID NIH HHS/United States GR - R01 AI143740/AI/NIAID NIH HHS/United States GR - R01 AI155558/AI/NIAID NIH HHS/United States GR - R01 AI130043/AI/NIAID NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, N.I.H., Intramural PT - Research Support, Non-U.S. Gov't DEP - 20211109 PL - United States TA - Sci Signal JT - Science signaling JID - 101465400 RN - EC 3.1.3.48 (PTPN6 protein, human) RN - EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 6) SB - IM MH - *Killer Cells, Natural MH - Protein Tyrosine Phosphatase, Non-Receptor Type 6 PMC - PMC8791782 MID - NIHMS1768481 COIS- Competing interests: K.C.H. is a member of the Wugen Scientific Advisory Board. The other authors declare that they have no competing interests. EDAT- 2021/11/10 06:00 MHDA- 2022/01/18 06:00 PMCR- 2022/05/09 CRDT- 2021/11/09 17:16 PHST- 2021/11/09 17:16 [entrez] PHST- 2021/11/10 06:00 [pubmed] PHST- 2022/01/18 06:00 [medline] PHST- 2022/05/09 00:00 [pmc-release] AID - 10.1126/scisignal.abe5380 [doi] PST - ppublish SO - Sci Signal. 2021 Nov 9;14(708):eabe5380. doi: 10.1126/scisignal.abe5380. Epub 2021 Nov 9.