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      Human CD8 + T-Cell Populations That Express Natural Killer Receptors

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          Abstract

          CD8 + T cells are activated by TCRs that recognize specific cognate Ags, while NK-cell activation is regulated by a balance between signals from germline-encoded activating and inhibitory NK receptors. Through these different processes of Ag recognition, CD8 + T cells and NK cells play distinct roles as adaptive and innate immune cells, respectively. However, some human CD8 + T cells have been found to express activating or inhibitory NK receptors. CD8 + T-cell populations expressing NK receptors straddle the innate-adaptive boundary with their innate-like features. Recent breakthrough technical advances in multi-omics analysis have enabled elucidation of the unique immunologic characteristics of these populations. However, studies have not yet fully clarified the heterogeneity and immunological characteristics of each CD8 + T-cell population expressing NK receptors. Here we aimed to review the current knowledge of various CD8 + T-cell populations expressing NK receptors, and to pave the way for delineating the landscape and identifying the various roles of these T-cell populations.

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          Most cited references80

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          NK cell recognition.

          The integrated processing of signals transduced by activating and inhibitory cell surface receptors regulates NK cell effector functions. Here, I review the structure, function, and ligand specificity of the receptors responsible for NK cell recognition.
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            HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C.

            The protein HLA-E is a non-classical major histocompatibility complex (MHC) molecule of limited sequence variability. Its expression on the cell surface is regulated by the binding of peptides derived from the signal sequence of some other MHC class I molecules. Here we report the identification of ligands for HLA-E. We constructed tetramers in which recombinant HLA-E and beta2-microglobulin were refolded with an MHC leader-sequence peptide, biotinylated, and conjugated to phycoerythrin-labelled Extravidin. This HLA-E tetramer bound to natural killer (NK) cells and a small subset of T cells from peripheral blood. On transfectants, the tetramer bound to the CD94/NKG2A, CD94/NKGK2B and CD94/NKG2C NK cell receptors, but did not bind to the immunoglobulin family of NK cell receptors (KIR). Surface expression of HLA-E was enough to protect target cells from lysis by CD94/NKG2A+ NK-cell clones. A subset of HLA class I alleles has been shown to inhibit killing by CD94/NKG2A+ NK-cell clones. Only the HLA alleles that possess a leader peptide capable of upregulating HLA-E surface expression confer resistance to NK-cell-mediated lysis, implying that their action is mediated by HLA-E, the predominant ligand for the NK cell inhibitory receptor CD94/NKG2A.
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              Anti-NKG2A mAb Is a Checkpoint Inhibitor that Promotes Anti-tumor Immunity by Unleashing Both T and NK Cells

              Summary Checkpoint inhibitors have revolutionized cancer treatment. However, only a minority of patients respond to these immunotherapies. Here, we report that blocking the inhibitory NKG2A receptor enhances tumor immunity by promoting both natural killer (NK) and CD8+ T cell effector functions in mice and humans. Monalizumab, a humanized anti-NKG2A antibody, enhanced NK cell activity against various tumor cells and rescued CD8+ T cell function in combination with PD-x axis blockade. Monalizumab also stimulated NK cell activity against antibody-coated target cells. Interim results of a phase II trial of monalizumab plus cetuximab in previously treated squamous cell carcinoma of the head and neck showed a 31% objective response rate. Most common adverse events were fatigue (17%), pyrexia (13%), and headache (10%). NKG2A targeting with monalizumab is thus a novel checkpoint inhibitory mechanism promoting anti-tumor immunity by enhancing the activity of both T and NK cells, which may complement first-generation immunotherapies against cancer.
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                Author and article information

                Journal
                Immune Netw
                Immune Netw
                IN
                Immune Network
                The Korean Association of Immunologists
                1598-2629
                2092-6685
                February 2023
                20 February 2023
                : 23
                : 1
                : e8
                Affiliations
                [1 ]Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea.
                [2 ]Genome Insight, Inc., Daejeon 34051, Korea.
                [3 ]The Center for Viral Immunology, Korea Virus Research Institute, Institute for Basic Science (IBS), Daejeon 34126, Korea.
                Author notes
                Correspondence to Eui-Cheol Shin. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), 245 Daehak-ro, Yuseong-gu, Daejeon 34141, Korea. ecshin@ 123456kaist.ac.kr

                These authors contributed equally.

                Author information
                https://orcid.org/0000-0002-2043-6624
                https://orcid.org/0000-0003-3908-8698
                https://orcid.org/0000-0002-2602-7389
                https://orcid.org/0000-0002-6308-9503
                Article
                10.4110/in.2023.23.e8
                9995994
                36911797
                c589e0eb-c10d-4a28-8133-7489809a9c09
                Copyright © 2023. The Korean Association of Immunologists

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 28 December 2022
                : 07 February 2023
                : 07 February 2023
                Categories
                Review Article

                Immunology
                cd8-positive t-lymphocytes,natural killer cell receptors,cd56 antigen,receptors, kir,nkg2a receptor,nkg2c receptor

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