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What does it take to make a natural killer?

Nature Reviews Immunology volume 3, pages 413–425 (2003)Cite this article

Key Points

  • Natural killer (NK) cells respond to cytokines, stress signals, microbial products and molecules that are expressed on infected or transformed cells. They are therefore important in the defence against infection and cancer.

  • Although it is generally accepted that NK-cell generation takes place in the bone marrow of adults, the features that make the bone marrow well suited for NK-cell development remain ill-defined.

  • Haematopoietic stem cells (HSCs) successively restrict their potential to generate different blood cell lineages. Recently, commited NK-cell progenitors (NKPs) have been identified.

  • A two-step stromal cell-free culture system has defined the minimal cytokine requirements for NK-cell generation in vitro. In a first phase, HSCs become committed to the NK-cell lineage; and in the second phase, they become killer cells under the influence of interleukin-15.

  • The final maturation of NK cells, including acquisition of expression of MHC-specific inhibitory and activating receptors, depends on contact with stromal cells.

  • A better understanding of NK-cell development could improve the use of these effector cells in diverse pathological states.

Abstract

We know how B and T cells develop, what they 'see' and the receptors they 'see with'. By contrast, and despite an unprecedented increase in the number of receptors and ligands known to regulate the activity of natural killer (NK) cells, we still have many questions regarding how these cells develop. Nevertheless, we are beginning to understand the transcriptional programmes of NK-cell maturation and the role of the effector functions of NK cells in the regulation of immune responses. An improved knowledge of NK-cell development in mice and humans might be useful to harness the power of these natural killers in the clinic to fight autoimmune diseases, infection and cancer.

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Figure 1: The where and when of NK-cell development.
Figure 2: NK-cell development in vitro.
Figure 3: A working model for NK-cell development.

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Acknowledgements

F.C. and J.P.D. are supported by grants from the Pasteur Institute, Inserm, Association pour la Recherche sur le Cancer, Ligue National Contre le Cancer, and the Fondation pour la Recherche Medicale. M.A.C. is supported in part by grant from the United States National Cancer Institute. We thank C. A. Vosshenrich, B. Becknell and T. Ranson for critical reading of the review.

Author information

Authors and Affiliations

  1. Department of Immunology, Cytokines and Lymphoid Development Unit, Pasteur Institute, 25 Rue du Dr Roux, Paris, 75724, France

    Francesco Colucci & James P. Di Santo

  2. Department of Internal Medicine, Division of Haematology and Oncology, The James Cancer Hospital and Comprehensive Cancer Centre, The Ohio State University, Columbus, 43210, Ohio, USA

    Michael A. Caligiuri

Authors
  1. Francesco Colucci
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  2. Michael A. Caligiuri
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Correspondence to James P. Di Santo.

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DATABASES

LocusLink

2B4

CCR7

CD2

CD7

CD16

CD34

CD56

CD94

CD161

c-KIT

c-KIT ligand

ETS1

FLT3

FLT3L

GATA3

ID2

ID3

IFN-γ

IL-2

IL-7

IL-8

IL-15

IL-21

IL-2Rβ

IRF1

KIR

L-selectin

LTα

LTβR

Ly49

NEMO

NKG2A

NKR-P1

PU.1

SAP

TRAIL

FURTHER INFORMATION

Michael A. Caligiuri's lab

James P. Di Santo's lab

Glossary

HAEMATOPOIETIC STEM CELLS

(HSCs). These are defined functionally as the one cell that is capable of self-renewing and generating all of the cell types present in the blood. Common myeloid progenitors, common lymphoid progenitors, early lymphoid progenitors and natural-killer-cell precursors are committed progenitors that are derived from HSCs.

NK-CELL PRECURSORS

(NKPs). Cells that can differentiate into natural killer (NK) cells but no other haematopoietic lineage. The expression of the interleukin-2 receptor β-chain by early lymphoid precursors seems to indicate commitment to the NK-cell lineage.

DI GEORGE SYNDROME

A clinical syndrome that is characterized by congenital aplasia or hypoplasia of the thymus and the parathyroid glands, associated with facial and cardiovascular malformations. In 85% of cases, it is caused by a de novo deletion of chromosome 22q11.2

DEVELOPMENTAL INTERMEDIATES

Phenotypically defined cell types that are known to be part of a developmental pathway, and that, on the basis of expression of cell-surface markers or gene-expression profiles, can be placed precisely in that pathway.

COMMITMENT OF HAEMATOPOIETIC STEM CELLS

Lineage commitment is a progressive process that results in loss of the ability to differentiate into multiple lineages. This process is associated with a change in the gene-expression profiles and often correlates with the acquisition of expression of specific cell-surface markers, which are useful for the identification of particular stages of development.

NK-CELL REPERTOIRE

The collection of cell-surface receptors expressed by a population of NK cells. Individual NK cells can express combinations of activating and inhibitory NK-cell receptors; the sum total of different NK-cell clones in the organism defines the 'repertoire'. NK-cell receptors are expressed in a sequential, but stochastic manner during maturation in the bone marrow.

SELF-TOLERANCE

With reference to NK-cell differentiation, the capacity of NK cells to recognize self-MHC molecules (typically classical and non-classical MHC class I gene products) through inhibitory receptors with the resultant downregulation of NK-cell effector functions.

EFFECTOR FUNCTIONS

NK cells were discovered for their ability to spontaneously kill tumour cell lines in vitro. Besides natural cytotoxicity, NK cells can mediate other forms of killing, such as antibody-dependent cellular cytotoxicity. NK cells are also potent producers of interferon-γ, tumour-necrosis factor and granulocyte–macrophage colony-stimulating factor, which prime the adaptive immune system, stimulate myeloid growth and mediate anti-virus and cytotoxic effects. NK cells can also produce chemokines, which attract other cells of the immune system.

CMPS, CLPS AND ELPS

A group of haematopoietic precursors that are committed to either the myeloid (common myeloid progenitor), or the lymphoid (common lymphoid progenitor or early lymphoid progenitor) lineage. CMPs give rise to monocytes, granulocytes, erytrocytes, megakaryocytes and mast cells, whereas CLPs/ELPs give rise to B, T and NK cells.

HOMEOSTASIS

A self-regulating process by which biological systems maintain stability, while adjusting to conditions that are optimal for survival. When applied to lymphocyte subsets, this refers to the mechanisms that regulate cell numbers in the peripheral pool.

MISSING-SELF HYPOTHESIS

Almost 20 years ago, Klas Kärre predicted the existence of inhibitory receptors expressed by NK cells that recognize self-MHC class I molecules87. The lack of expression of the relevant MHC by target cells (missing self) consequently activates NK cells and results in target-cell elimination.

ANTIBODY-DEPENDENT CELLULAR CYTOTOXICITY

(ADCC). Cells that are coated with antibodies are targeted and destroyed by NK cells, macrophages and granulocytes. On NK cells, ADCC is mediated by the Fc receptor complex (CD16).

NKT CELLS

T cells that express antigen receptors of limited variability and that share markers and functions with NK cells. NKT cells are potent producers of cytokines and are heterogeneous in terms of target recognition, anatomical localization and functions.

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Colucci, F., Caligiuri, M. & Di Santo, J. What does it take to make a natural killer?. Nat Rev Immunol 3, 413–425 (2003). https://doi.org/10.1038/nri1088

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