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Natural killer cells and dendritic cells: rendezvous in abused tissues

Key Points

  • Human natural killer (NK) cells interact with dendritic cells (DCs) in inflamed peripheral tissues.

  • NK cells induce DC maturation, but they also have cytolytic activity against immature DCs. So, NK cells regulate the progression of DC maturation by selecting the most appropriate antigen-presenting cells to undergo migration to secondary lymphoid compartments.

  • The cell-surface NK-cell receptor that is responsible for DC recognition and killing is the NKp30 molecule, a member of the natural cytotoxicity receptor (NCR) family.

  • In turn, DCs, which release interleukin-12 (IL-12) and IL-15 after antigen uptake, induce NK-cell activation. So, DCs can regulate NK-cell proliferation and lymphokine release in response to pathogens or tumours.

  • NK cells that express CC-chemokine receptor 7 (CCR7) migrate to secondary lymphoid compartments, where they exert quality control (editing) of mature DCs.

  • In patients with acute myeloid leukaemia (AML) who have received a bone-marrow transplant, alloreactive NK cells, derived from killer-cell immunoglobulin-like receptor (KIR)-mismatched donors, can kill leukaemic cells (graft-versus-leukaemia effect) and can prevent graft-versus-host reactions by killing DCs of the patient.

Abstract

Natural killer (NK) cells and dendritic cells (DCs) are two types of specialized cell of the innate immune system, the reciprocal interaction of which results in a potent, activating cross-talk. For example, DCs can prime resting NK cells, which, in turn, after activation, might induce DC maturation. However, NK cells negatively regulate the function of DCs also by killing immature DCs in peripheral tissues. Moreover, a subset of NK cells, after migration to secondary lymphoid tissues, might have a role in the editing of mature DCs based on the selective killing of mature DCs that do not express optimal surface densities of MHC class I molecules. So, cognate interactions between NK cells and DCs provide a coordinated mechanism that is involved not only in the regulation of innate immunity, but also in the promotion of appropriate downstream adaptive responses for defence against pathogens.

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Figure 1: A model of NK-cell–DC cross-talk in injured tissues.
Figure 2: A model of NK-cell-mediated editing of DCs in lymph nodes.
Figure 3: Allogeneic NK cells characterized by a KIR mismatch can kill DCs in leukaemic patients receiving bone-marrow transplants.

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Acknowledgements

I am grateful to A. Lanzavecchia and L. Moretta for helpful discussions and for critical reading of this manuscript. I also thank T. Baffi for secretarial assistance. This work was supported by grants from the Associazione Italiana per la Ricerca sul Cancro (AIRC), Istituto Superiore di Sanità (ISS), Capagnia San Paolo (Torino, Italy). Also, the financial support of Telethon-Italy is gratefully acknowledged.

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DATABASES

Cancer.gov

leukaemia

LocusLink

CCL3

CCL4

CCL5

CCL19

CCL21

CCL22

CCR1

CCR5

CCR6

CCR7

CD36

CD40

CD40L

CD58

CD80

CD83

CD86

CD94

CXCL8

CXCL9

CXCL10

CXCL11

CXCL12

CXCR1

CX3CL1

CX3CR1

GM-CSF

HLA-A

HLA-B

HLA-C

HLA-E

IFN-γ

IL-2

IL-4

IL-12

IL-15

KIR2DL1–KIR2DL3

KIR3DL1

L-selectin

MICA

MICB

NKG2A

NKp30

NKp44

NKp46

TGF-β

TNF

ULBP1

ULBP2

ULBP3

Glossary

KILLER-CELL IMMUNOGLOBULIN-LIKE RECEPTORS

(KIRs). These receptors, encoded on human chromosome 19, are expressed by NK-cell subsets and by a minor population of T cells. Inhibitory KIRs have locus and allele specificity for MHC class I molecules.

CD94–NKG2A

A heterodimeric inhibitory receptor that is expressed by a main NK-cell subset and by certain T cells. Both CD94 and NKG2A molecules are encoded on human chromosome 12. This receptor recognizes HLA-E molecules that present signal-sequence peptides derived from most MHC class I alleles, except for HLA-BW4 alleles.

NKp30

A member of the natural cytotoxicity receptor family that is involved in the activation of natural-killer-cell-mediated cytotoxicity. It is encoded on human chromosome 6 and its signalling depends on association with ζ and γ immunoreceptor tyrosine-based activation motif (ITAM)-containing polypeptides.

MHC CLASS I POLYPEPTIDE-RELATED SEQUENCE A/B (MICA/MICB).

These are ligands for human NKG2D. They are closely related stress-inducible molecules that are encoded in the human MHC. These molecules are expressed by tumours of epithelial origin and certain melanomas.

UL16-BINDING PROTEINS

(ULBPs). These are ligands for human NKG2D and for the human cytomegalovirus-encoded UL16 protein. They are glycosylphosphatidylinositol (GPI)-linked molecules that — unlike most members of the MHC class I family, which map to human chromosome 6p21 — map to chromosome 6q25. Three members of this family have been identified (ULBP1, ULBP2 and ULBP3).

HEAT-SHOCK PROTEINS

(HSPs). Intracellular proteins that mediate many functions that are crucial for cellular survival. In eukaryotic cells, they are found in the cytosol, nucleus, mitochondria and endoplasmic reticulum. Under cellular stress, their level of expression is increased in many types of cell.

SLC AND ELC

These are ligands for the CCR7 chemokine receptor. SLC (secondary lymphoid-tissue chemokine) is also known as CCL21, and ELC (Epstein–Barr virus-induced molecule 1 ligand chemokine) is also known as CCL19. Both are involved in lymphocyte recruitment through high endothelial venules to lymph nodes.

ALLOREACTIVE NK CELLS

These cells can kill allogeneic haematopoietic targets. This is owing to the expression on their surface of killer-cell immunoglobulin-like receptors (KIRs) that cannot recognize the MHC class I alleles that are expressed by the allogeneic cells.

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Moretta, A. Natural killer cells and dendritic cells: rendezvous in abused tissues. Nat Rev Immunol 2, 957–965 (2002). https://doi.org/10.1038/nri956

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