HLA-E regulates NKG2C+ natural killer cell function through presentation of a restricted peptide repertoire

Lauterbach, Nina; Wieten, Lotte; Popeijus, Herman E.; Voorter, Christina E.M.; Tilanus, Marcel G.J.

doi:10.1016/j.humimm.2015.09.003

Cited by 46 publications

(50 citation statements)

References 52 publications

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“…Interestingly, we found that NKG2C surface expression was significantly lower on NK cells stimulated with the anti-NKG2C Ab relative to those stimulated with the anti-NK-G2A/C Ab ( Figure 1A). This effect may be due to downmodulation or internalization of NKG2C, a phenomenon that has been previously described upon NK cell stimulation with HLA-E:G peptide complexes (15,44). For direct measurement of proliferation, we labeled NK cells with CellTrace dye prior to culturing and repeated these culture experiments.…”

Section: Resultsmentioning

confidence: 98%

Chronic stimulation drives human NK cell dysfunction and epigenetic reprograming

Merino

Zhang

Dougherty

et al. 2019

Journal of Clinical Investigation

136

111

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Conflict of interest:FC consults for Fate Therapeutics and has received research funds from this relationship. JSM serves on the Scientific Advisory Board (SAB) and consults for GT BioPharma and Fate Therapeutics. He has received research funds from these relationships. JSM also serves on the SAB for CytoSen and Onkimmune. BRB declares a financial conflict with Tmunity and Kadmon Corporation. He also serves on the SAB for GT Biopharma, Magenta Therapeutics, and Five Prime Therapeutics. He consults for Regeneron and Equillium Inc. None of these companies had a role in funding this research. All conflicts are managed according to institutional policies. Figure 1. Chronic stimulation through NKG2C expands adaptive NK cells. CD3/CD19-depleted PBMCs from HCMV-seropositive donors were cultured for 7 days with 10 ng/ml IL-15 and PBS, IgG2b isotype Ab, anti-NKG2A/C Ab, or anti-NKG2C Ab. (A) Representative FACS plots and summary data showing the percentages of NK cell subsets defined by expression of CD57 and NKG2C before and after a 7-day culture (n = 7). Results are from 3 independent experiments. (B) NK cells were labeled with CellTrace dye prior to culturing. Shown are FACS plots of representative donor cells stratified by CD57 and NKG2C expression and summary data (n = 6). Results are from 3 independent experiments. *P ≤ 0.05 by paired t test. P values for multiple group comparisons (A, each group vs. PBS; B, each group vs. IgG2b isotype Ab) were adjusted using the Hommel method.Study approval. The present studies involving the use of human peripheral blood products were reviewed and approved by the IRB of the University of Minnesota under protocol 9709M00134. All blood donors provided informed consent prior to donation according to Memorial Blood Bank policies. All blood samples were deidentified prior to arrival in the laboratory.

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Section: Resultsmentioning

confidence: 98%

Chronic stimulation drives human NK cell dysfunction and epigenetic reprograming

Merino

Zhang

Dougherty

et al. 2019

Journal of Clinical Investigation

136

111

View full text Add to dashboard Cite

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“…We know that the interaction KIR-HLA has two sides of KIR and HLA. For example overexpression of HLA-E on surface of colorectal cancer cells can result in inhibition of NKs [53] and such patients have better survival from the disease [54]; of course the receptor of HLA-E is CD94/NKG2a [55], [56]. KIR2DL1 and 2DS1 interact with HLA-C2, and KIR2DL2, 2DL3 and 2DS2 interact with HLA-C1 [57]; so every mathematical predict do not occur.…”

Section: Resultsmentioning

confidence: 99%

Colorectal cancer and the KIR genes in the human genome: A meta-analysis

et al. 2016

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Colorectal cancer is one of the most common types of inflammation-based cancers and is occurred due to growth and spread of cancer cells in colon and/or rectum. Previously genetic association of cell cycle genes, both proto-oncogenes and the tumor suppressors has been proved. But there were few studies about association of immune related genes such as killer-cell immunoglobulin-like receptors (KIRs). Thus we intend to perform a meta-analysis to find the association of different genes of KIR and susceptibility to be affected by colorectal cancer. The overall population of the four studies investigated in our meta-analysis was 953 individuals (470 individuals with colorectal cancer and 483 individuals in control groups). After the analyses, we concluded that colorectal cancer is affected by KIR2DS5 and also there were no protecting gene. This result shows the inflammatory basis of this cancer. In other words, in contrast to leukemia and blood cancers, colorectal cancers seem to be affected by hyper activity of natural killer-cells (NKs). Whys and therefore of this paradox, is suggested to be investigated further.

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“…Subtle differences in HLA‐E bound peptides can lead to NK cell activation, thus, it is conceivable that HCMV peptides are recognized by NKG2C via HLA‐E presentation, thereby promoting preferential expansion of NKG2C + cells . Certain HCMV derived peptides loaded on HLA‐E do promote degranulation of NK cells bearing NKG2C, in the absence of its inhibitory counterpart NKG2A, consistent with the predominant phenotype of functionally mature NKG2C + CD57 + NK cells [, ]. The cytokine environment and possibly the HLA‐E/NKG2C stimulatory axis may be subdued in our in vitro system compared to others.…”

Section: Resultsmentioning

confidence: 99%

NK cells generate memory‐type responses to human cytomegalovirus‐infected fibroblasts

2017

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Natural killer (NK) cells are cytotoxic lymphocytes that selectively respond against abnormal cells. Human cytomegalovirus (HCMV) infection causes expansion of NKG2C CD57 NK cells in vivo and NKG2C NK cells proliferate when cultured with HCMV-infected cells. This raises the possibility of an NK-cell subset selectively responding against a specific pathogen and accruing memory. To test this possibility, we compared proliferation, natural cytotoxicity and interferon-γ (IFN-γ) production of NK cells from HCMV-seropositive and HCMV-seronegative individuals co-cultured with HCMV-infected or uninfected MRC-5 cells. There was no significant difference in proliferation of NK cells from HCMV-seropositive or seronegative individuals against uninfected MRC-5 cells, but significantly more NK cells from the HCMV-seropositive group proliferated in response to HCMV-infected MRC-5 cells. Natural cytotoxicity of NK cells against K562 cells increased following co-culture with HCMV-infected versus uninfected MRC-5 only for the HCMV-seropositive group. After co-culture with HCMV-infected MRC-5 cells, proliferating NK cells from HCMV-seropositive donors selectively produced IFN-γ when re-exposed to HCMV-infected MRC-5 cells. Both NKG2C and NKG2C NK cells proliferated in co-culture with HCMV-infected MRC-5 cells, with the fraction of proliferating NKG2C NK cells directly correlating with the circulating NKG2C fraction. These data illustrate an at least partly NKG2C-independent human NK-cell memory-type response against HCMV.

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HLA-E regulates NKG2C+ natural killer cell function through presentation of a restricted peptide repertoire

Cited by 46 publications

References 52 publications

Chronic stimulation drives human NK cell dysfunction and epigenetic reprograming

Chronic stimulation drives human NK cell dysfunction and epigenetic reprograming

Colorectal cancer and the KIR genes in the human genome: A meta-analysis

NK cells generate memory‐type responses to human cytomegalovirus‐infected fibroblasts

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