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Human NK cells: surface receptors, inhibitory checkpoints, and translational applications

Cellular & Molecular Immunologyvolume 16pages430441 (2019) | Download Citation


NK cells play important roles in innate defenses against viruses and in the control of tumor growth and metastasis. The regulation/induction of NK cell function is mediated by an array of activating or inhibitory surface receptors. In humans, major activating receptors involved in target cell killing are the natural cytotoxicity receptors (NCRs) and NKG2D. Activating receptors recognize ligands that are overexpressed or expressed de novo upon cell stress, viral infection, or tumor transformation. The HLA-class I-specific inhibitory receptors, including KIRs recognizing HLA-class I allotypic determinants and CD94/NKG2A recognizing the class-Ib HLA-E, constitute a fail-safe mechanism to avoid unwanted NK-mediated damage to healthy cells. Other receptors such as PD-1, primarily expressed by activated T lymphocytes, are important inhibitory checkpoints of immune responses that ensure T-cell tolerance. PD-1 also may be expressed by NK cells in cancer patients. Since PD-1 ligand (PD-L1) may be expressed by different tumors, PD-1/PD-L1 interactions inactivate both T and NK cells. Thus, the reliable evaluation of PD-L1 expression in tumors has become a major issue to select patients who may benefit from therapy with mAbs disrupting PD-1/PD-L1 interactions. Recently, NKG2A was revealed to be an important checkpoint controlling both NK and T-cell activation. Since most tumors express HLA-E, mAbs targeting NKG2A has been used alone or in combination with other therapeutic mAbs targeting PD-1 or tumor antigens (e.g., EGFR), with encouraging results. The translational value of NK cells and their receptors is evidenced by the extraordinary therapeutic success of haploidentical HSCT to cure otherwise fatal high-risk leukemias.

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This study is dedicated to Alessandro Moretta, who sadly passed away on February 17, 2018. His seminal discoveries of inhibitory and activating NK receptors made it possible to understand how NK cells function. Many of the issues described in this review are based on his pioneering studies. We greatly miss his scientific insight and even more his humanity and smile. Supported by grants awarded by Associazione Italiana per la Ricerca sul Cancro (AIRC)-Special Program Metastatic disease: the key unmet need in oncology 5 per mille 2018 Id. 21147 (S.S. and L.M.), AIRC IG2017 Id. 20312 (S.S.), AIRC IG2017 Id.19920 (L.M.), RC-2018 OPBG (P.V. and L.M.); 5 × 1000 Italian Ministry of Health 2015 (M.C.M); and Ministero della Salute RF-2013, GR-2013-02356568 (P.V.).

Author information


  1. Department of Experimental Medicine (DIMES) and Centre of Excellence for Biomedical Research (CEBR), University of Genoa, Genoa, Italy

    • Simona Sivori
    •  & Maria Cristina Mingari
  2. Department of Immunology, IRCCS Bambino Gesù Children’s Hospital, Rome, Italy

    • Paola Vacca
    •  & Lorenzo Moretta
  3. Department of Research and Diagnostics, Istituto G. Gaslini, Genoa, Italy

    • Genny Del Zotto
  4. Department of Diagnostics and Public Health, University of Verona, Verona, Italy

    • Enrico Munari
  5. Department of Pathology, Sacro Cuore Don Calabria, Negrar, VR, Italy

    • Enrico Munari
  6. UOC Immunologia, IRCCS Ospedale Policlinico San Martino Genova, Genoa, Italy

    • Maria Cristina Mingari


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The authors declare no competing interests.

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Correspondence to Lorenzo Moretta.

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