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      Durable natural killer cell response after three doses of SARS-CoV-2 inactivated vaccine in HIV-infected individuals

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          Abstract

          Background:

          Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine can induce a potent cellular and humoral immune response to protect against SARS-CoV-2 infection. However, it was unknown whether SARS-CoV-2 vaccination can induce effective natural killer (NK) cell response in people living with human immunodeficiency virus (PLWH) and healthy individuals.

          Methods:

          Forty-seven PLWH and thirty healthy controls (HCs) inoculated with SARS-CoV-2 inactivated vaccine were enrolled from Beijing Youan Hospital in this study. The effect of SARS-CoV-2 vaccine on NK cell frequency, phenotype, and function in PLWH and HCs was evaluated by flow cytometry, and the response of NK cells to SARS-CoV-2 Omicron Spike (SARS-2-OS) protein stimulation was also evaluated.

          Results:

          SARS-CoV-2 vaccine inoculation elicited activation and degranulation of NK cells in PLWH, which peaked at 2 weeks and then decreased to a minimum at 12 weeks after the third dose of vaccine. However, in vitro stimulation of the corresponding peripheral blood monocular cells from PLWH with SARS-2-OS protein did not upregulate the expression of the aforementioned markers. Additionally, the frequencies of NK cells expressing the activation markers CD25 and CD69 in PLWH were significantly lower than those in HCs at 0, 4 and 12 weeks, but the percentage of CD16 + NK cells in PLWH was significantly higher than that in HCs at 2, 4 and 12 weeks after the third dose of vaccine. Interestingly, the frequency of CD16 + NK cells was significantly negatively correlated with the proportion of CD107a + NK cells in PLWH at each time point after the third dose. Similarly, this phenomenon was also observed in HCs at 0, 2, and 4 weeks after the third dose. Finally, regardless of whether NK cells were stimulated with SARS-2-OS or not, we did not observe any differences in the expression of NK cell degranulation markers between PLWH and HCs.

          Conclusion:

          s:SARS-CoV-2 vaccine elicited activation and degranulation of NK cells, indicating that the inoculation of SARS-CoV-2 vaccine enhances NK cell immune response.

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          Exploring the NK cell platform for cancer immunotherapy

          Jacob Myers, Jeffrey S. Miller (2020)
          Natural killer (NK) cells are cytotoxic lymphocytes of the innate immune system that are capable of killing virally infected and/or cancerous cells. Nearly 20 years ago, NK cell-mediated immunotherapy emerged as a safe and effective treatment approach for patients with advanced-stage leukaemia. Subsequently, the field of NK cell-based cancer therapy has grown exponentially and currently constitutes a major area of immunotherapy innovation. In general, the development of NK cell-directed therapies has two main focal points: optimizing the source of therapeutic NK cells for adoptive transfer and enhancing NK cell cytotoxicity and persistence in vivo. A wide variety of sources of therapeutic NK cells are currently being tested clinically, including haploidentical NK cells, umbilical cord blood NK cells, stem cell-derived NK cells, NK cell lines, adaptive NK cells, cytokine-induced memory-like NK cells and chimeric antigen receptor NK cells. A plethora of methods to augment the cytotoxicity and longevity of NK cells are also under clinical investigation, including cytokine-based agents, NK cell-engager molecules and immune-checkpoint inhibitors. In this Review, we highlight the variety of ways in which diverse NK cell products and their auxiliary therapeutics are being leveraged to target human cancers. We also identify future avenues for NK cell therapy research.
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            NK cell CD16 surface expression and function is regulated by a disintegrin and metalloprotease-17 (ADAM17).

            Rizwan Romee, Bree Foley, Todd R. Lenvik … (2013)
            The Fc receptor CD16 is present on essentially all CD56(dim) peripheral blood natural killer (NK) cells. Upon recognition of antibody-coated cells it delivers a potent signal to NK cells, which eliminate targets through direct killing and cytokine production. Here we investigated the regulation of CD16 surface expression after NK cell activation. Cytokine activation and target cell stimulation led to marked decreases in CD16 expression. Activation of CD56(dim) NK cells by cross-linking CD16 with antibodies resulted in a loss of CD16 and CD62L, which correlated with increased interferon-γ production. A disintegrin and metalloprotease-17 (ADAM17) is shown to be expressed by NK cells, and its selective inhibition abrogated CD16 and CD62L shedding, and led to enhanced interferon-γ production, especially when triggering was delivered through CD16. Fc-induced production of cytokines by NK cells exposed to rituximab-coated B cell targets was also enhanced by ADAM17 inhibition. This supports an important role for targeting ADAM17 to prevent CD16 shedding and improve the efficacy of therapeutic antibodies. Our findings demonstrate that over-activation of ADAM17 in NK cells may be detrimental to their effector functions by down-regulating surface expression of CD16 and CD62L.
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              CD107a as a functional marker for the identification of natural killer cell activity.

              Galit Alter, Jessica M. Malenfant, Marcus Altfeld (2004)
              Natural killer (NK) cells are a subset of lymphocytes that play a central role in the innate immune response to tumors and infections. An important limitation in the field of NK research is attributable to the deficit of assays available for the detection of the functional activity of NK cells. Recently, lysosomal-associated membrane protein-1 (LAMP-1 or CD107a) has been described as a marker of CD8+ T-cell degranulation following stimulation. Here we describe CD107a as a marker of NK cell functional activity using multi-parameter flow cytometry. CD107a is significantly upregulated on the surface of NK cells following stimulation with MHC devoid targets. Additionally, CD107a expression correlates with both cytokine secretion and NK cell-mediated lysis of target cells. However, as well as being coordinately expressed on nearly all cytokine secreting cells, CD107a was also expressed on a large subset of NK cells that did not secrete cytokine following stimulation. These data suggest that employing CD107a as a marker of NK cell functional activity may allow for the identification of a large fraction of activated NK cells that may degranulate in the absence of cytokine secretion. Cumulatively, the data presented here demonstrate that CD107a is a sensitive marker of NK cell activity.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Chin Med J (Engl)
                Journal ID (iso-abbrev): Chin Med J (Engl)
                Journal ID (publisher-id): CM9
                Title: Chinese Medical Journal
                Publisher: Lippincott Williams & Wilkins (Hagerstown, MD )
                ISSN (Print): 0366-6999
                ISSN (Electronic): 2542-5641
                Publication date (Electronic): 27 November 2023
                Publication date (Print): 20 December 2023
                Volume: 136
                Issue: 24
                Pages: 2948-2959
                Affiliations
                [ 1 ]Beijing Key Laboratory for HIV/AIDS Research, Sino-French Joint Laboratory for Research on Humoral Immune Response to HIV Infection, Clinical and Research Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
                [ 2 ]National Center for AIDS/STD Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China
                [ 3 ]Tian Yuan Studio, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
                Author notes
                Correspondence to: Tong Zhang, Beijing Key Laboratory for HIV/AIDS Research, Sino-French Joint Laboratory for Research on Humoral Immune Response to HIV Infection, Clinical and Research Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China E-Mail: zt_doc@ 123456ccmu.edu.cn ;
                Hao Wu, Beijing Key Laboratory for HIV/AIDS Research, Sino-French Joint Laboratory for Research on Humoral Immune Response to HIV Infection, Clinical and Research Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China E-Mail: whdoc@ 123456ccmu.edu.cn ;
                Cong Jin, National Center for AIDS/STD Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China E-Mail: jinc@ 123456chinaaids.cn
                Article
                Publisher ID: CMJ-2023-1345 Accession ID: 00007
                DOI: 10.1097/CM9.0000000000002947
                PMC ID: 10752448
                PubMed ID: 38018259
                SO-VID: fdf50f0f-74ce-4e4a-a07e-b5c380871d35
                Copyright © Copyright © 2023 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0

                History
                Date received : 29 May 2023
                Categories
                Subject: Original Article
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                OPEN-ACCESS TRUE

                Keywords: hiv,sars-cov-2 inactivated vaccine,covid-19,omicron variant,nk cell response,immunologic memory
                Data availability:
                Keywords: hiv, sars-cov-2 inactivated vaccine, covid-19, omicron variant, nk cell response, immunologic memory

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