Lifespan socioeconomic context is associated with cytomegalovirus and late-differentiated CD8+ T and NK cells: Initial results in older adults.

OBJECTIVE: Lower socioeconomic status (SES) can accelerate immune aging; however, it is unknown whether and how lifespan socioeconomic context (SEC) -the relative wealth and quality of the communities an individual lives in across their lifespan- impacts immune aging. We examined the effects of childhood and adulthood SEC on late-differentiated immune cells and investigated the mediating and moderating role of cytomegalovirus (CMV), a key driver of immune aging. METHODS: Adults 60 years and older (N = 109) reported their addresses from birth to age 60, which were coded for county-level employment, education, and income to construct a latent SEC variable, averaged across ages 0-18 (childhood SEC) and 19-60 (adulthood SEC). Blood was drawn semiannually over 5 years for CMV serostatus and flow cytometry estimates of late-differentiated CD8+ T and natural killer (NK) cells. Models were adjusted for chronological age, time, gender, and individual SES (current income and education). RESULTS: Lower childhood SEC was associated with higher percentages of late-differentiated CD8+ T and NK cells via CMV seropositivity (indirect effects ps .015-.028). Additionally, an interaction between CMV serostatus and SEC on CD8+ T cell aging (p = .049) demonstrated that adulthood SEC was negatively associated with immune aging among CMV- but not CMV+ adults. CONCLUSIONS: Beyond current SES, socioeconomic context related to immune aging in distinct patterns by lifespan phase. Lower childhood SEC importantly may influence who acquires CMV, which in turn, predicts higher levels of immune aging, whereas higher adulthood SEC was protective against immune aging among CMV- older adults. These initial results need to be explored in larger samples.

Life stressors and immune aging: Protective effects of cognitive reappraisal.

Stressful life events may accelerate aspects of immune aging, but habitual use of an adaptive emotion regulation strategy, cognitive reappraisal, may attenuate these effects. This study examined whether cognitive reappraisal moderates the associations between life stressor frequency and stressor desirability on aspects of immune aging, including late-differentiated CD8+ T and natural killer (NK) cells and inflammatory markers (IL-6, TNF-α, and CRP), both between and within people in a longitudinal sample of 149 older adults (mean age = 77.8, range: 64-92 years). Participants reported stressful life events, use of cognitive reappraisal, and provided blood semiannually for up to 5 years to assess aspects of immune aging. Multilevel models, adjusted for demographic and health covariates, tested the between-person (stable, trait-like differences) and within-person associations (dynamic fluctuations) among life stressors and reappraisal on immune aging. Experiencing more frequent life stressors than usual was associated with higher levels of late-differentiated NK cells within person, but this effect was accounted for by experiencing health-related stressors. Unexpectedly, experiencing more frequent and less desirable stressors were associated with lower average levels of TNF-α. As expected, reappraisal moderated the associations between life stressors and late-differentiated NK cells between people and IL-6 within people. Specifically, older adults who experienced less desirable stressors but also used more reappraisal had significantly lower proportions of late-differentiated NK cells on average and lower levels of IL-6 within-person. These results suggest cognitive reappraisal may play a protective role in attenuating the effects of stressful life events on aspects of innate immune aging in older adults.

Perceived stress, cytomegalovirus titers, and late-differentiated T and NK cells: Between-, within-person associations in a longitudinal study of older adults.

Cytomegalovirus (CMV) and psychological stress are implicated as drivers of immunological aging. It is unknown, however, whether associations among CMV titers, stress, and immune aging are more stable or dynamic over time. The present investigation tested the between-person (stable differences) and within-person (dynamic fluctuations) associations of CMV titers and perceived stress on late-differentiated T and natural killer (NK) peripheral blood cells in a longitudinal study of older adults aged 64-92 years (N = 149). Participants reported stress levels and provided blood biannually for 2.5 years (up to 5 waves per person) to assess CMV IgG titers and composites of late-differentiated CD8 T cells (CD28- and CD57 + subsets) and CD56dim NK cells (CD57+, NKG2C+, and FcεRIγ- subsets). In multilevel models that controlled for demographic variables, higher CMV titers were associated with higher proportions and counts of aged T and NK cells between people and lower counts of aged T cells within people. Perceived stress was associated with higher counts of aged T cells between people, but was not associated with aged NK cells. A significant interaction between stress and CMV titers on T cells between people indicated that older adults with lower stress levels and lower CMV titers had the lowest proportions of late-differentiated T cells, whereas those with higher stress levels had high proportions, regardless of CMV control. Our results provide evidence for longer-term, between-person associations among CMV titers, stress, and immunological aging, rather than dynamic within-person associations. We propose that targeting factors that promote low, stable perceived stress in older adults may retard T cell differentiation and ultimately support healthy aging.

Human natural killer cell microRNA: differential expression of MIR181A1B1 and MIR181A2B2 genes encoding identical mature microRNAs.

Natural killer (NK) and T lymphocytes share many properties, yet only NK cells respond rapidly to infection and cancer without pre-activation. We found that few microRNAs (miRNAs) differed significantly between human NK and T cells. Among those miRNAs, miR-181a and miR-181b levels rose during NK cell differentiation. Prior studies indicate that miR-181a and miR-181b are critical for human NK cell development and are co-transcribed from genes on chromosome 1 (MIR181A1B1) and on chromosome 9 (MIR181A2B2). We mapped human MIR181A1B1 and MIR181A2B2 transcription start sites to 78.3 kb and 34.0 kb upstream of the mature miRNAs, generating predominantly unspliced transcripts of 80-127 kb and ~60 kb, respectively. Unlike mouse thymocytes, human T cells expressed both MIR181A1B1 and MIR181A2B2. We tested the hypothesis that NK cells differentially transcribe the two genes during development and in response to immune regulatory cytokines. During NK-cell differentiation, MIR181A2B2 expression rose markedly and exceeded that of MIR181A1B1. TGF-ß treatment increased NK-cell MIR181A2B2 transcription, whereas IL-2, IL-15 and IL-12/IL-18 treatments upregulated MIR181A1B1. The MIR181A2B2 promoter was strongly transactivated by SMAD3 and SMAD4 transcription factors, suggesting that TGF-ß signaling upregulates MIR181A2B2 expression, at least in part, through SMAD-dependent promoter activation.

Differential transcription factor use by the KIR2DL4 promoter under constitutive and IL-2/15-treated conditions.

KIR2DL4 is unique among human KIR genes in expression, cellular localization, structure, and function, yet the transcription factors required for its expression have not been identified. Using mutagenesis, EMSA, and cotransfection assays, we identified two redundant Runx binding sites in the 2DL4 promoter as essential for constitutive 2DL4 transcription, with contributions by a cyclic AMP response element (CRE) and initiator elements. IL-2- and IL-15-stimulated human NK cell lines increased 2DL4 promoter activity, which required functional Runx, CRE, and Ets sites. Chromatin immunoprecipitation experiments show that Runx3 and Ets1 bind the 2DL4 promoter in situ. 2DL4 promoter activity had similar transcription factor requirements in T cells. Runx, CRE, and Ets binding motifs are present in 2DL4 promoters from across primate species, but other postulated transcription factor binding sites are not preserved. Differences between 2DL4 and clonally restricted KIR promoters suggest a model that explains the unique 2DL4 expression pattern in human NK cells.

Human leukocyte antigen Bw4 and Bw6 epitopes recognized by antibodies and natural killer cells.

PURPOSE OF REVIEW: To describe the structural basis of human leukocyte antigen (HLA) Bw4 and Bw6 epitopes that are recognized by antibodies and the KIR3DL1 natural killer cell receptor. RECENT FINDINGS: Molecular modeling and X-ray crystallography have refined our understanding of Bw4 and Bw6. These epitopes had been defined by comparison of HLA allele sequences and by site-directed mutagenesis. Anti-Bw4 and anti-Bw6 antibodies and KIR3DL1 receptors recognize HLA α-1 α-helix residues 77-83 in combination with other HLA regions. The variability of HLA sequences within the 77-83 region and at other sites indicates that the Bw4 epitope is complex. Adding complexity, HLA-bound peptides influence Bw4 and Bw6 epitopes. These structures are recognized by diverse antibodies and KIR3DL1 allotypes. This diversity allowed a Bw4 patient to produce anti-Bw4 antibody without breaking self-tolerance. SUMMARY: Bw4 and Bw6 epitopes are best regarded as families of related structures that are recognized by a diverse array of antibodies and KIR3DL1 allotypes.

Human NK cells proliferate and die in vivo more rapidly than T cells in healthy young and elderly adults.

NK cells are essential for health, yet little is known about human NK turnover in vivo. In both young and elderly women, all NK subsets proliferated and died more rapidly than T cells. CD56(bright) NK cells proliferated rapidly but died relatively slowly, suggesting that proliferating CD56(bright) cells differentiate into CD56(dim) NK cells in vivo. The relationship between CD56(dim) and CD56(bright) proliferating cells indicates that proliferating CD56(dim) cells both self-renew and are derived from proliferating CD56(bright) NK cells. Our data suggest that some dying CD56(dim) cells become CD16(+)CD56(-) NK cells and that CD16(-)CD56(low) NK cells respond rapidly to cellular and cytokine stimulation. We propose a model in which all NK cell subsets are in dynamic flux. About half of CD56(dim) NK cells expressed CD57, which was weakly associated with low proliferation. Surprisingly, CD57 expression was associated with higher proliferation rates in both CD8(+) and CD8(-) T cells. Therefore, CD57 is not a reliable marker of senescent, nonproliferative T cells in vivo. NKG2A expression declined with age on both NK cells and T cells. Killer cell Ig-like receptor expression increased with age on T cells but not on NK cells. Although the percentage of CD56(bright) NK cells declined with age and the percentage of CD56(dim) NK cells increased with age, there were no significant age-related proliferation or apoptosis differences for these two populations or for total NK cells. In vivo human NK cell turnover is rapid in both young and elderly adults.

Cutting edge: microRNA-181 promotes human NK cell development by regulating Notch signaling.

MicroRNAs (miRs) have recently been identified as important regulators of gene expression at the posttranscriptional level. Although it has clearly been established that miRs influence the ontogeny of several immune cell lineages, the role of individual miRs during NK cell development has not been described. In this study, we show that miR-181 expression levels have a profound impact on the development of human NK cells from CD34(+) hematopoietic progenitor cells and IFN-γ production in primary CD56(+) NK cells. We also demonstrate that nemo-like kinase (NLK), an inhibitor of Notch signaling, is a target of miR-181 in NK cells, and knockdown of NLK mirrors the developmental effect of miR-181 overexpression. We conclude that miR-181 promotes NK cell development, at least in part, through the suppression of NLK, providing an important link between miRs and Notch signaling.

Resources and lymphocyte terminal maturity among older adults.

OBJECTIVE: Women's financial resources were associated with more terminal maturity in natural killer lymphocytes, generally associated with loss of proliferative potential, during the "Great Recession". This preregistered analysis expanded on that finding in a longitudinal design including both genders and examining the role of cytomegalovirus (CMV) serostatus. METHOD: Older adults (N = 138, 57% women) were assessed longitudinally during 2012-2017; including self-reported psychological, social, financial, and status-skill resources, CMV antibody titers and serostatus, and assessment of T and natural killer lymphocyte terminal maturity (LTM). RESULTS: Neither total nor financial resources were associated with LTM. Adjusting only for age, more psychological resources (e.g., meaning, hope, humor) were associated with lower T LTM (percent: γ = -1.11 [-1.78, -.44]; number: γ = -.99 [-1.70, -.27]). There were no significant interactions with age, gender, or CMV serostatus; however, additionally adjusting for serostatus reduced the effect of psychological resources (percent: γ = -.41 [-93, .12]; number: (γ = -.40 [-.94, .13]). CONCLUSIONS: Outside the context of the "Great Recession", psychological resources but not financial resources were associated with terminal maturity in T cells, a relationship related to CMV serostatus. Further studies in different and more diverse samples, and in different eras, are needed to understand what resources are most protective against immunological aging, when, and for whom. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

The role of late-differentiated T cells, a proxy for IFN-γ-production, in older adults' social networks.

Interferon-γ (IFN-γ), an inflammatory biomarker that promotes antiviral immunity, may be a prerequisite for sociability. IFN-γ production in older adulthood is driven by late-differentiated CD8+ T cells, particularly CD28-and CD57+ subsets, which increase with age, reduce immune response, and increase chronic disease risk. The present study investigated the relationship between late-differentiated T cells (LDTC) and sociability in a longitudinal study of healthy aging. 139 older adults (Mage = 77.95, range 65-93; 58% female, 57% college educated, and 94% Caucasian) provided data at up to 10 occasions (M = 7). Social network size and diversity and cytomegalovirus (CMV) status were collected at every wave. Percentage of LDTC was measured at up to 4 waves and averaged for each participant. There were no significant main effects of LDTC or interactions between LDTC and time on social network size or diversity. Adjustment for baseline age, gender, and sensitivity analyses including CMV and imputed data did not change results. IFN-γ may not play a role in dictating social behavior in older adults. Alternately, LDTC may not have accurately represented circulating levels of IFN-γ. Future work should continue exploring IFN-γ and social behavior, particularly as it relates to age-related changes. The role of IFN-γ-producing, late-differentiated T cells in older adults' social networks.

Proteasome regulation of ULBP1 transcription.

Killer lymphocytes recognize stress-activated NKG2D ligands on tumors. We examined NKG2D ligand expression in head and neck squamous cell carcinoma (HNSCC) cells and other cell lines. HNSCC cells typically expressed MHC class I chain-related gene A (MICA), MICB, UL16-binding protein (ULBP)2, and ULBP3, but they were uniformly negative for cell surface ULBP1 and ULBP4. We then studied how cancer treatments affected NKG2D ligand expression. NKG2D ligand expression was not changed by most cancer-relevant treatments. However, bortezomib and other proteasome inhibitor drugs with distinct mechanisms of action dramatically and specifically up-regulated HNSCC ULBP1 mRNA and cell surface protein. Proteasome inhibition also increased RNA for ULBP1 and other NKG2D ligands in nontransformed human keratinocytes. Proteasome inhibitor drugs increased ULBP1 transcription by acting at a site in the 522-bp ULBP1 promoter. Although the DNA damage response pathways mediated by ATM (ataxia-telangiectasia, mutated) and ATR (ATM and Rad3-related) signaling had been reported to up-regulate NKG2D ligand expression, we found that ULBP1 up-regulation was not inhibited by caffeine and wortmannin, inhibitors of ATM/ATR signaling. ULBP1 expression in HNSCC cells was not increased by several ATM/ATR activating treatments, including bleomycin, cisplatin, aphidicolin, and hydroxyurea. Ionizing radiation caused ATM activation in HNSCC cells, but high-level ULBP1 expression was not induced by gamma radiation or UV radiation. Thus, ATM/ATR signaling was neither necessary nor sufficient for high-level ULBP1 expression in human HNSCC cell lines and could not account for the proteasome effect. The selective induction of ULBP1 expression by proteasome inhibitor drugs, along with variable NKG2D ligand expression by human tumor cells, indicates that NKG2D ligand genes are independently regulated.

Gender Differences in Urothelial Bladder Cancer: Effects of Natural Killer Lymphocyte Immunity.

Men are more likely to develop cancer than women. In fact, male predominance is one of the most consistent cancer epidemiology findings. Additionally, men have a poorer prognosis and an increased risk of secondary malignancies compared to women. These differences have been investigated in order to better understand cancer and to better treat both men and women. In this review, we discuss factors that may cause this gender difference, focusing on urothelial bladder cancer (UBC) pathogenesis. We consider physiological factors that may cause higher male cancer rates, including differences in X chromosome gene expression. We discuss how androgens may promote bladder cancer development directly by stimulating bladder urothelium and indirectly by suppressing immunity. We are particularly interested in the role of natural killer (NK) cells in anti-cancer immunity.

DNA methylation maintains allele-specific KIR gene expression in human natural killer cells.

Killer immunoglobulin-like receptors (KIR) bind self-major histocompatibility complex class I molecules, allowing natural killer (NK) cells to recognize aberrant cells that have down-regulated class I. NK cells express variable numbers and combinations of highly homologous clonally restricted KIR genes, but uniformly express KIR2DL4. We show that NK clones express both 2DL4 alleles and either one or both alleles of the clonally restricted KIR 3DL1 and 3DL2 genes. Despite allele-independent expression, 3DL1 alleles differed in the core promoter by only one or two nucleotides. Allele-specific 3DL1 gene expression correlated with promoter and 5' gene DNA hypomethylation in NK cells in vitro and in vivo. The DNA methylase inhibitor, 5-aza-2'-deoxycytidine, induced KIR DNA hypomethylation and heterogeneous expression of multiple KIR genes. Thus, NK cells use DNA methylation to maintain clonally restricted expression of highly homologous KIR genes and alleles.

Differential Fuel Requirements of Human NK Cells and Human CD8 T Cells: Glutamine Regulates Glucose Uptake in Strongly Activated CD8 T Cells.

CD8 T cells and NK cells are the two major cytotoxic lymphocytes that carry out cell-mediated immunity and regulate other immune responses. However, we do not completely understand human CD8 T cell and NK cell metabolic requirements and they have not been compared in the same experiments. We activated human CD8 T cells by two anti-CD3/CD28 mAb methods, and we stimulated both CD8 T cells and NK cells with IL-12/IL-18. When glucose (Glc) could not be used, human CD8 T cells either died or became hypofunctional, depending upon the anti-CD3/CD28 activation method. In contrast, Glc starvation did not decrease the percentage of IL-12/IL-18-stimulated human NK cells that made IFN-γ. NK cells were relatively fuel resilient and used Glc, glutamine (Gln), fatty acid, or acetate to power IFN-γ expression. Surprisingly, strongly activated human CD8 T cells required Gln for glycolysis and Glc uptake. We showed that human CD8 T cells regulate Glc uptake by a novel mechanism related to the TXNIP pleiotropic protein. These conditions may be relevant to septic patients who have high blood Glc but low Gln. Under the conditions tested, Gln did not change human NK cell TXNIP expression. Our experiments reveal fundamental differences in human CD8 T cell and NK cell metabolism and the fuels needed for IFN-γ production.

Mouse fetal and embryonic liver cells differentiate human umbilical cord blood progenitors into CD56-negative natural killer cell precursors in the absence of interleukin-15.

OBJECTIVE: Human natural killer (NK) cell maturation involves the orderly acquisition of NK cell receptors. Our aim was to understand how stromal interactions and cytokines are important in this developmental process. MATERIALS AND METHODS: Human umbilical cord blood (UCB) CD34(+)/Lin(-)/CD38(-) cells were cultured on two murine stromal cell lines (AFT024 and EL08-1D2) in a switch culture to study NK cell development. RESULTS: When human progenitors were cultured on AFT024 with interleukin (IL)-3 and Flt3 ligand (Flt3L) in the absence of interleukin (IL)-15, NK cell differentiation occurred, albeit at low frequency. These conditions favored the accumulation of CD56(-) NK cell precursors (CD34(+)CD7(-), CD34(+)CD7(+), and CD34(-)CD7(+) cells), which are populations rare in adult blood but abundant in fresh UCB. In secondary culture, addition of IL-3 or IL-3 + Flt3L to IL-15 increased the absolute number of CD56(+) NK cells from precursors and the acquisition of CD94 and killer immunoglobulin-like receptors (KIR). To further explore the microenvironment in early NK cell maturation, a cell line derived from murine embryonic liver (EL08-1D2) was studied. NK cell development and KIR acquisition was superior with EL08-1D2, which supported the differentiation of NK cell precursors, NK cell commitment, and proliferation. CONCLUSION: Although the earliest events in NK cell maturation do not require exogenous human IL-15, it is required at a later stage of NK cell commitment. At a minimum, murine stroma, IL-3, and Flt3L are required to recapitulate early NK cell development and differentiation into distinct NK cell precursors. EL08-1D2 induces KIR acquisition suggesting that extrinsic signals in NK cell development are conserved between mouse and man.

A longitudinal study of the stability, variability, and interdependencies among late-differentiated T and NK cell subsets in older adults.

The stability and variability of older adults' late-differentiated peripheral blood T and natural killer (NK) cells over time remains incompletely quantified or understood. We examined the variability and change over time in T and NK cell subsets in a longitudinal sample of older adults; the effects of sex, cytomegalovirus (CMV) serostatus, and chronic disease severity on immune levels and trajectories; and interdependencies among T and NK cell subsets. Older adults (N = 149, age 64-94 years, 42% male) provided blood every 6 months for 2.5 years (up to 5 waves) to evaluate late-differentiated CD8 T cells (CD28-, CD57+) and CD56dimNK cells (CD57+, NKG2C+, FcɛRIγ-). In multilevel models, most of the variance in immune subsets reflected stable differences between people. However, CD56dimNK cell subsets (CD57+ and FcɛRIγ-) also increased with age, whereas T cell subsets did not. Independent of age, all subsets examined were higher in CMV-positive older adults. Men had higher levels of CD56dim CD57+ than women. Chronic disease was not associated with any immune subset investigated. T and NK cell subsets correlated within each cell type, but interdependencies differed by CMV serostatus. Our results suggest the accumulation of these stable cell populations may be driven less by chronological aging, even less by chronic disease severity, and more by CMV, which may differentially skew T and NK cell differentiation.

Human Body Composition and Immunity: Visceral Adipose Tissue Produces IL-15 and Muscle Strength Inversely Correlates with NK Cell Function in Elderly Humans.

Natural killer (NK) lymphocyte-mediated cytotoxicity and cytokine secretion control infections and cancers, but these crucial activities decline with age. NK cell development, homeostasis, and function require IL-15 and its chaperone, IL-15 receptor alpha (IL-15Rα). Macrophages and dendritic cells (DC) are major sources of these proteins. We had previously postulated that additional IL-15 and IL-15Rα is made by skeletal muscle and adipose tissue. These sources may be important in aging, when IL-15-producing immune cells decline. NK cells circulate through adipose tissue, where they may be exposed to local IL-15. The objectives of this work were to determine (1) if human muscle, subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) are sources of IL-15 and IL-15 Rα, and (2) whether any of these tissues correlate with NK cell activity in elderly humans. We first investigated IL-15 and IL-15Rα RNA expression in paired muscle and SAT biopsies from healthy human subjects. Both tissues expressed these transcripts, but IL-15Rα RNA levels were higher in SAT than in skeletal muscle. We also investigated tissue obtained from surgeries and found that SAT and VAT expressed equivalent amounts of IL-15 and IL-15Rα RNA, respectively. Furthermore, stromal vascular fraction cells expressed more IL-15 RNA than did adipocytes. To test if these findings related to circulating IL-15 protein and NK cell function, we tested 50 healthy adults aged > 70 years old. Plasma IL-15 levels significantly correlated with abdominal VAT mass in the entire cohort and in non-obese subjects. However, plasma IL-15 levels did not correlate with skeletal muscle cross-sectional area and correlated inversely with muscle strength. Plasma IL-15 did correlate with NK cell cytotoxic granule exocytosis and with CCL4 (MIP-1ß) production in response to NKp46-crosslinking. Additionally, NK cell responses to K562 leukemia cells correlated inversely with muscle strength. With aging, immune function declines while infections, cancers, and deaths increase. We propose that VAT-derived IL-15 and IL-15Rα is a compensatory NK cell support mechanism in elderly humans.

The effect of sex on immune cells in healthy aging: Elderly women have more robust natural killer lymphocytes than do elderly men.

Immune gender differences have been reported, but are little studied in elderly humans. We compared monocyte and lymphocyte subsets, along with soluble immune mediators in healthy men and women over the age of 70. We also measured natural killer (NK) lymphocyte cytotoxic granule exocytosis, chemokine synthesis, and cytokine synthesis in response to a variety of stimuli. Elderly women had significantly more circulating B cells than men, whereas men had more CD4 central memory T cells and higher monocyte levels. Plasma adiponectin levels were higher in women, plasma retinol-binding protein 4 levels were higher in men, but there were no significant gender differences in C-reactive protein, IL-15, or sphingosine-1-phosphate. Women had a higher ratio of immature CD56(bright) NK cells to mature CD56(dim) NK cells, indicating a gender difference in NK cell maturation in the elderly. Comparing sexes, female mature NK cells had more vigorous cytotoxic granule responses to K562 leukemia cells and IFN-γ responses to NKp46 crosslinking. Moreover, female NK cells were more likely to produce MIP-1ß in response to a variety of stimuli. These data show that gender influences NK cell activity in elderly humans.

Data correlations between gender, cytomegalovirus infection and T cells, NK cells, and soluble immune mediators in elderly humans.

We describe a cohort of 50 elderly subjects, age at least 70 years. We present gender-specific findings in T lymphocyte markers and soluble immune mediators. We show the correlation between cytomegalovirus infection status with CD56(dim) NK cell responses to a variety of stimuli and with CD56(bright)/CD56(dim) NK cell ratio. We also present the correlation of retinol binding protein (RBP)-4 plasma levels with NK cell responses and we explore the relationship between gender and adiponectin, 25(OH)D (vitamin D), and RBP4 in affecting CD56(dim) NK cell responses. These data are discussed in Al-Attar et al. (2016) [1].

Reciprocal age related change in natural killer cell receptors for MHC class I.

Natural killer (NK) cells are essential for healthy aging. NK cell activation is controlled by MHC class I-specific CD94/NKG2 receptors and killer immunoglobulin-like receptors (KIR). To assess NK cytotoxic function in isolation from MHC receptor engagement, we measured the ability of purified NK cells to kill mouse P815 target cells in the presence of anti-CD16 mAb. CD16-mediated cytotoxicity did not change with age, indicating that NK activation and cytotoxic granule release remained functional. We then investigated MHC class I receptor expression on NK cells. There was an age related decrease in CD94 and NKG2A expression and a reciprocal age related increase in KIR expression. NKG2A expression also declined with age on CD56(+) T cells. CD94/NKG2A receptor function was proportional to expression, indicating that NK cell inhibitory signaling pathways were intact. NKG2A and KIR expression were complementary, suggesting that CD94/NKG2A function could substitute for inhibitory KIR function during polyclonal NK cell development in both young and elderly adults. The distinct roles of CD94/NKG2A and KIR receptors suggest that shifting MHC class I receptor expression patterns reflect age related changes in NK cell and CD56(+) T cell turnover and function in vivo.