Human NK cells display major phenotypic and functional changes over the life span

Abstract

SummaryAging is generally associated with an increased predisposition to infectious diseases and cancers, related in part to the development of immune senescence, a process that affects all cell compartments of the immune system. Although many studies have investigated the effects of age on natural killer (NK) cells, their conclusions remain controversial because the diverse health status of study subjects resulted in discordant findings. To clarify this situation, we conducted the first extensive phenotypic and functional analysis of NK cells from healthy subjects, comparing NK cells derived from newborn (cord blood), middle-aged (18-60 years), old (60-80 years), and very old (80-100 years) subjects. We found that NK cells in cord blood displayed specific features associated with immaturity, including poor expression of KIR and LIR-1 ⁄ ILT-2 and high expression of both NKG2A and IFN-c. NK cells from older subjects, on the other hand, preserved their major phenotypic and functional characteristics, but with their mature features accentuated. These include a profound decline of the CD56 bright subset, a specific increase in LIR-1 ⁄ ILT-2, and a perfect recovering of NK-cell function following IL2-activation in very old subjects. We conclude that the preservation of NK cell features until very advanced age may contribute to longevity and successful aging.

Deciphering the killer‐cell immunoglobulin‐like receptor system at super‐resolution for natural killer and T‐cell biology

“…Similar observation was made for T cells, in which KIR expression is virtually absent in CD4 and CD8 naive T cells and reaches its maximal level in differentiated effector memory T cells 2, 5, 151, 152. Accordingly, KIR expression is low in less mature cord blood NK and T cells compared with healthy adult control cells 153, 154…”

The Innate Immune System and Aging: What is the Contribution to Immunosenescence ?

“…The IL-2 induced NK cell proliferation is decreased with aging [81]. Many cytokines and chemokines produced by NK cells are also decreased with aging, such as IL-2, IL-8 [88], while that of IFN-γ seems to be maintained [84]. This decreased production of cytokines contributes to the altered activation of macrophages with aging resulting in decreased microbicidal and tumoricidal activities.…”

“…Studies in very healthy elderly populations revealed that the NK cell number tends to increase while the cytotoxicity is not significantly affected [81][82][83] and this is contributing to longevity and successful aging [84,85]. Other studies in unselected elderly populations showed decreased NK cell functions with aging which was associated with higher incidence of infectious diseases [86,87].…”

Independent skewing of the T cell and NK cell compartments associated with cytomegalovirus infection suggests division of labor between innate and adaptive immunity

“…The NK cell analysis included NKG2A and NKG2C, which are inhibitory and activating receptors, respectively, binding to the nonclassical human leukocyte antigen (HLA) class I molecule HLA-E (Lanier 1998;Moretta et al 1996). We also assessed the frequency of ILT-2 + and CD57 + NK cells, which both have been demonstrated to have an increasing frequency on NK cells throughout life (Le Garff-Tavernier et al 2010). ILT-2 binds the CMVencoded UL18 protein and is together with CD57 upregulated on terminally differentiated T and NK cells following acute CMV infection (Northfield et al 2005;Lopez-Verges et al 2011).…”

“…In this age group, it is yet uncertain whether an inversed CD4/CD8 ratio corresponds to increased mortality and truly defines an IRP. Since natural killer (NK) cells have an important role in the defense against viral infections and display profound changes throughout the lifespan (Le Garff-Tavernier et al 2010;Biron et al 1996;Beziat et al 2013), we set out to examine whether expansion of CD8 + T cells seen in individuals with an inversed CD4/CD8 ratio is coupled to a parallel skewing of the NK compartment. NK cells belong to the innate arm of the immune system and provide a rapid first line of defense against viral infections and may also contribute to the clearance of transformed cells (Lanier 2005;Vivier et al 2008).…”