Aging of the Immune System: Focus on Natural Killer Cells Phenotype and Functions

Abstract

Aging is the greatest risk factor for nearly all major chronic diseases, including cardiovascular diseases, cancer, Alzheimer's and other neurodegenerative diseases of aging. Age-related impairment of immune function (immunosenescence) is one important cause of age-related morbidity and mortality, which may extend beyond its role in infectious disease. One aspect of immunosenescence that has received less attention is age-related natural killer (NK) cell dysfunction, characterized by reduced cytokine secretion and decreased target cell cytotoxicity, accompanied by and despite an increase in NK cell numbers with age. Moreover, recent studies have revealed that NK cells are the central actors in the immunosurveillance of senescent cells, whose age-related accumulation is itself a probable contributor to the chronic sterile low-grade inflammation developed with aging ("inflammaging"). NK cell dysfunction is therefore implicated in the increasing burden of infection, malignancy, inflammatory disorders, and senescent cells with age. This review will focus on recent advances and open questions in understanding the interplay between systemic inflammation, senescence burden, and NK cell dysfunction in the context of aging. Understanding the factors driving and enforcing NK cell aging may potentially lead to therapies countering age-related diseases and underlying drivers of the biological aging process itself.

Keywords: aging; cytokines; elderly; frailty; immune system; immunosenescence; inflammation; natural killer cells (NK cells); senescence.

Figure 1

Scheme of NK cell signaling after formation of immunological synapse (IS). Interaction of activating receptor with cognate ligand leads to phosphorylation of cytoplasmic tail and recruitment of PI3K [61,120]. Pathway (A) activation of PI3K and PLC lead to downstream signaling via MAPK and NFκB pathways, respectively, thus facilitating the production and secretion of cytokines, such as IFN-γ. Activation of MAPK signaling also contributes to MTOC migration and the polarization of lytic granules. Pathway (B). Conversion of phosphatidylinositol-4, 5-bisphosphate (PIP2) to phosphatidylinositol-3, 4, 5-triphosphate (PIP3) allows for subsequent generation of the secondary messenger inositol trisphosphate (IP3) via phospholipase C (PLC) [117]. IP3 contributes to the release of internal calcium stores from the smooth endoplasmic reticulum [123], which in turn facilitates mitochondrial migration to IS and influx of extracellular calcium via the ORAI1 transporter [118,119]. Additionally, the microtubule organization center (MTOC) migrates towards the IS and allows for efficient transport of lytic granules (secretory lysosomes) to travel to the IS [124,125]. Lastly, lytic granules fuse with the NK cell membrane in a calcium-dependent manner and release perforin and granzymes into the IS [126]. These proteins form holes in the target cell membrane and induce apoptosis.