Human NK cells

From surface receptors to clinical applications

Research output: Contribution to journalArticle

Abstract

Natural killer (NK) cells play a major role in innate defenses against pathogens, primarily viruses, and are also thought to be part of the immunosurveillance against tumors. They express an array of surface receptors that mediate NK cell function. The human leukocytes antigen (HLA) class I-specific inhibitory receptors allow NK cells to detect and kill cells that have lost or under-express HLA class I antigens, a typical feature of tumor or virally infected cells. However, NK cell activation and induction of cytolytic activity and cytokine production depends on another important checkpoint, namely the expression on target cells of ligands recognized by activating NK receptors. Despite their potent cytolytic activity, NK cells frequently fail to eliminate tumors. This is due to mechanisms of tumor escape, determined by the tumor cells themselves or by tumor-associated cells (i.e. the tumor microenvironment) via the release of soluble suppressive factors or the induction of inhibitory loops involving induction of regulatory T cells, M2-polarized macrophages and myeloid-derived suppressor cells. The most important clinical application involving NK cells is the cure of high-risk leukemias in the haplo-identical hematopoietic stem cell transplant (HSCT) setting. NK cells originated from hematopoietic stem cells (HSC) of HLA-haploidentical donors may express Killer Immunoglobulin-like receptors (KIRs) that are mismatched with the HLA class I alleles of the recipient. This allows NK cells to kill leukemia blasts residual after the conditioning regimen, while sparing normal cells (that do not express ligands for activating NK receptors). More recent approaches based on the specific removal of TCR α/β+ T cells and of CD19+ B cells, allow the infusion, together with CD34+ HSC, of mature KIR+ NK cells and of TCR γ/δ+ T cells, both characterized by a potent anti-leukemia activity. This greatly reduces the time interval necessary to obtain alloreactive, KIR+ NK cells derived from donor HSC. Another promising approach is based on the use of anti-KIR blocking monoclonal antibodies (mAbs), rendering alloreactive any KIR+ NK cells.

Original languageEnglish
JournalImmunology Letters
DOIs
Publication statusAccepted/In press - May 11 2016

Fingerprint

Cell Surface Receptors
Natural Killer Cells
KIR Receptors
HLA Antigens
Hematopoietic Stem Cells
Natural Killer Cell Receptors
Leukemia
Neoplasms
Tumor Escape
Ligands
T-Lymphocytes
Immunologic Monitoring
Histocompatibility Antigens Class I
Blocking Antibodies
Tumor Microenvironment
Regulatory T-Lymphocytes
B-Lymphocytes
Alleles
Macrophages
Monoclonal Antibodies

Keywords

  • Hematopoietic stem cell transplantation (HSCT)
  • Innate lymphoid cells (ILC)
  • NK cells
  • Tumor microenvironment

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

@article{1947aa42a2b74407b894132d4052b058,
title = "Human NK cells: From surface receptors to clinical applications",
abstract = "Natural killer (NK) cells play a major role in innate defenses against pathogens, primarily viruses, and are also thought to be part of the immunosurveillance against tumors. They express an array of surface receptors that mediate NK cell function. The human leukocytes antigen (HLA) class I-specific inhibitory receptors allow NK cells to detect and kill cells that have lost or under-express HLA class I antigens, a typical feature of tumor or virally infected cells. However, NK cell activation and induction of cytolytic activity and cytokine production depends on another important checkpoint, namely the expression on target cells of ligands recognized by activating NK receptors. Despite their potent cytolytic activity, NK cells frequently fail to eliminate tumors. This is due to mechanisms of tumor escape, determined by the tumor cells themselves or by tumor-associated cells (i.e. the tumor microenvironment) via the release of soluble suppressive factors or the induction of inhibitory loops involving induction of regulatory T cells, M2-polarized macrophages and myeloid-derived suppressor cells. The most important clinical application involving NK cells is the cure of high-risk leukemias in the haplo-identical hematopoietic stem cell transplant (HSCT) setting. NK cells originated from hematopoietic stem cells (HSC) of HLA-haploidentical donors may express Killer Immunoglobulin-like receptors (KIRs) that are mismatched with the HLA class I alleles of the recipient. This allows NK cells to kill leukemia blasts residual after the conditioning regimen, while sparing normal cells (that do not express ligands for activating NK receptors). More recent approaches based on the specific removal of TCR α/β+ T cells and of CD19+ B cells, allow the infusion, together with CD34+ HSC, of mature KIR+ NK cells and of TCR γ/δ+ T cells, both characterized by a potent anti-leukemia activity. This greatly reduces the time interval necessary to obtain alloreactive, KIR+ NK cells derived from donor HSC. Another promising approach is based on the use of anti-KIR blocking monoclonal antibodies (mAbs), rendering alloreactive any KIR+ NK cells.",
keywords = "Hematopoietic stem cell transplantation (HSCT), Innate lymphoid cells (ILC), NK cells, Tumor microenvironment",
author = "Lorenzo Moretta and Gabriella Pietra and Paola Vacca and Daniela Pende and Francesca Moretta and Alice Bertaina and Mingari, {Maria Cristina} and Franco Locatelli and Alessandro Moretta",
year = "2016",
month = "5",
day = "11",
doi = "10.1016/j.imlet.2016.05.007",
language = "English",
journal = "Immunology Letters",
issn = "0165-2478",
publisher = "Elsevier",

}

TY - JOUR

T1 - Human NK cells

T2 - From surface receptors to clinical applications

AU - Moretta, Lorenzo

AU - Pietra, Gabriella

AU - Vacca, Paola

AU - Pende, Daniela

AU - Moretta, Francesca

AU - Bertaina, Alice

AU - Mingari, Maria Cristina

AU - Locatelli, Franco

AU - Moretta, Alessandro

PY - 2016/5/11

Y1 - 2016/5/11

N2 - Natural killer (NK) cells play a major role in innate defenses against pathogens, primarily viruses, and are also thought to be part of the immunosurveillance against tumors. They express an array of surface receptors that mediate NK cell function. The human leukocytes antigen (HLA) class I-specific inhibitory receptors allow NK cells to detect and kill cells that have lost or under-express HLA class I antigens, a typical feature of tumor or virally infected cells. However, NK cell activation and induction of cytolytic activity and cytokine production depends on another important checkpoint, namely the expression on target cells of ligands recognized by activating NK receptors. Despite their potent cytolytic activity, NK cells frequently fail to eliminate tumors. This is due to mechanisms of tumor escape, determined by the tumor cells themselves or by tumor-associated cells (i.e. the tumor microenvironment) via the release of soluble suppressive factors or the induction of inhibitory loops involving induction of regulatory T cells, M2-polarized macrophages and myeloid-derived suppressor cells. The most important clinical application involving NK cells is the cure of high-risk leukemias in the haplo-identical hematopoietic stem cell transplant (HSCT) setting. NK cells originated from hematopoietic stem cells (HSC) of HLA-haploidentical donors may express Killer Immunoglobulin-like receptors (KIRs) that are mismatched with the HLA class I alleles of the recipient. This allows NK cells to kill leukemia blasts residual after the conditioning regimen, while sparing normal cells (that do not express ligands for activating NK receptors). More recent approaches based on the specific removal of TCR α/β+ T cells and of CD19+ B cells, allow the infusion, together with CD34+ HSC, of mature KIR+ NK cells and of TCR γ/δ+ T cells, both characterized by a potent anti-leukemia activity. This greatly reduces the time interval necessary to obtain alloreactive, KIR+ NK cells derived from donor HSC. Another promising approach is based on the use of anti-KIR blocking monoclonal antibodies (mAbs), rendering alloreactive any KIR+ NK cells.

AB - Natural killer (NK) cells play a major role in innate defenses against pathogens, primarily viruses, and are also thought to be part of the immunosurveillance against tumors. They express an array of surface receptors that mediate NK cell function. The human leukocytes antigen (HLA) class I-specific inhibitory receptors allow NK cells to detect and kill cells that have lost or under-express HLA class I antigens, a typical feature of tumor or virally infected cells. However, NK cell activation and induction of cytolytic activity and cytokine production depends on another important checkpoint, namely the expression on target cells of ligands recognized by activating NK receptors. Despite their potent cytolytic activity, NK cells frequently fail to eliminate tumors. This is due to mechanisms of tumor escape, determined by the tumor cells themselves or by tumor-associated cells (i.e. the tumor microenvironment) via the release of soluble suppressive factors or the induction of inhibitory loops involving induction of regulatory T cells, M2-polarized macrophages and myeloid-derived suppressor cells. The most important clinical application involving NK cells is the cure of high-risk leukemias in the haplo-identical hematopoietic stem cell transplant (HSCT) setting. NK cells originated from hematopoietic stem cells (HSC) of HLA-haploidentical donors may express Killer Immunoglobulin-like receptors (KIRs) that are mismatched with the HLA class I alleles of the recipient. This allows NK cells to kill leukemia blasts residual after the conditioning regimen, while sparing normal cells (that do not express ligands for activating NK receptors). More recent approaches based on the specific removal of TCR α/β+ T cells and of CD19+ B cells, allow the infusion, together with CD34+ HSC, of mature KIR+ NK cells and of TCR γ/δ+ T cells, both characterized by a potent anti-leukemia activity. This greatly reduces the time interval necessary to obtain alloreactive, KIR+ NK cells derived from donor HSC. Another promising approach is based on the use of anti-KIR blocking monoclonal antibodies (mAbs), rendering alloreactive any KIR+ NK cells.

KW - Hematopoietic stem cell transplantation (HSCT)

KW - Innate lymphoid cells (ILC)

KW - NK cells

KW - Tumor microenvironment

UR - http://www.scopus.com/inward/record.url?scp=84970021945&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84970021945&partnerID=8YFLogxK

U2 - 10.1016/j.imlet.2016.05.007

DO - 10.1016/j.imlet.2016.05.007

M3 - Article

JO - Immunology Letters

JF - Immunology Letters

SN - 0165-2478

ER -