Age-related changes in natural killer cell repertoires: impact on NK cell function and immune surveillance - PubMed (original) (raw)

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Angela R Manser et al. Cancer Immunol Immunother. 2016 Apr.

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.

Keywords: Aging; KIR; NKG2; Natural killer cell.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1

Fig. 1

Age-related expression of KIR and NKG2A on NK cells. a Frequency of NKG2A+ (left panel) and KIR+NKG2A− (right panel) subsets in different age segments presented as Tukey box plots with variability (whiskers), outliers (single dots) and median (horizontal line inside the boxes). A frequency corridor of 30–50 %, encompassing the median of all adult age segments, is indicated in light gray. The data represent a comparative reanalysis of previously published sample sets from cord blood [40], pediatric [39] and adult [22, 41] healthy donors. b Distribution of the four NK cell subpopulations KIR−NKG2A− (mid-blue), KIR−NKG2A+ (light-blue), KIR+NKG2A+ (gray) and KIR+NKG2A− (dark-blue) in the indicated age groups compared to MDS patients (data from [22]). Statistical significance was determined using nonparametric one-way ANOVA, ***p < 0.001

Fig. 2

Fig. 2

Impact of aging on NK cell repertoire and function. The diagram summarizes age-dependent changes in the NK cell compartment and highlights important unanswered questions regarding the effect of aging on NK cell function. Changes in the frequency of KIR (green solid line) and NKG2A-expressing NK cells (red solid line) are primarily occurring during childhood and early adulthood and from there on remain stable in elderly and very old individuals. Nonetheless, in a minority of subjects, the KIR/NKG2A equilibrium is disturbed by HCMV-dependent clonal expansions or immaturity of NK cell repertoires due to impaired NK cell development, as exemplified in MDS patients. The data represent reanalysis of previously described samples [, –41]. The age-related putative increase in HCMV infection is depicted by a blue broken line

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