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Age-related changes in natural killer cell repertoires: impact on NK cell function and immune surveillance

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Abstract

A key feature of human natural killer (NK) cells, which enables efficient recognition of infected and malignant target cells, is the expression of HLA class I-specific receptors of the KIR and NKG2 gene families. Cell-to-cell variability in receptor expression leads to the formation of complex NK cell repertoires. As outlined here, NK cells go through major changes from newborns to adults characterized by downregulation of the inhibitory NKG2A receptor and concomitant upregulation of KIR family members. This process is completed in young adults, and in the majority of individuals, KIR/NKG2A repertoires remain remarkably stable until old age. Nonetheless, age-related factors have the potential to majorly influence the complexity of NK cell repertoires: Firstly infection with HCMV is associated with major clonal expansions of terminally differentiated NKG2C- and KIR-expressing NK cells in certain individuals. Secondly, ineffective hematopoiesis can lead to immature and less diversified NK cell repertoires as observed in myelodysplastic syndrome (MDS), a malignant disease of the elderly. Thus, whereas in the majority of elderly the NK cell compartment appears to be highly stable in terms of function and phenotype, in a minority of subjects a breakdown of NK cell repertoire diversity is observed that might influence immune surveillance and healthy aging.

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Abbreviations

ADCC:

Antibody-dependent cellular cytotoxicity

CD:

Cluster of differentiation

HCMV:

Human cytomegalovirus

HLA:

Human leukocyte antigen

HSPC:

Hematopoietic stem and progenitor cells

IFNγ:

Interferon-γ

IgG:

Immunoglobulin G

IL-2:

Interleukin-2

IPSS:

International prognostic scoring system

KIR:

Killer cell immunoglobulin-like receptor

MDS:

Myelodysplastic syndrome

MHC:

Major histocompatibility complex

MIC:

MHC class I chain-related protein

MSC:

Mesenchymal stem cells

NK:

Natural killer

TNFα:

Tumor necrose factor-α

ULBP:

UL-16-binding proteins

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Acknowledgments

This work was supported by funds by the Deutsche Krebshilfe (Grant 110351) and the Deutsche Forschungsgemeinschaft (research Grant UH 91/7-1).

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  1. Institute for Transplantation Diagnostics and Cell Therapeutics, Medical Faculty, Heinrich-Heine University Düsseldorf, Moorenstr. 5, 40225, Düsseldorf, Germany

    Angela R. Manser & Markus Uhrberg

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  1. Angela R. Manser
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Correspondence to Markus Uhrberg.

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This article is part of the Symposium-in-Writing “Natural killer cells, ageing and cancer”, a series of papers published in Cancer Immunology, Immunotherapy.

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Manser, A.R., Uhrberg, M. Age-related changes in natural killer cell repertoires: impact on NK cell function and immune surveillance. Cancer Immunol Immunother 65, 417–426 (2016). https://doi.org/10.1007/s00262-015-1750-0

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