Human NK cells display major phenotypic and functional changes over the life span Magali Le Garff-Tavernier, 1,2,3 Vivien Be ´ ziat, 1,2 Julie Decocq, 1,2,4 Virginie Siguret, 5,6 Fre ´ de ´ rique Gandjbakhch, 2,7 Eric Pautas, 8 Patrice Debre ´, 1,2 He ´ le ` ne Merle-Beral 2,3,9 and Vincent Vieillard 1,2 1 INSERM, UMR-S 945, F-75013, Paris, France 2 UPMC, Universite ´ Paris 06, F-75005, Paris, France 3 AP-HP, Ho ˆ pital Pitie ´ -Salpe ˆ trie ` re, Service d’He ´ matologie Biologique, F-75013, Paris, France 4 Laboratoire franc ¸ ais de fractionnement et des biotechnologies (LFB), F-91940, Les Ulis, France 5 AP-HP, Ho ˆ pital Charles-Foix, Laboratoire d’He ´ matologie, F-94205, Ivry sur Seine, France 6 Universite ´ Paris Descartes, F-75006, Paris, France 7 AP-HP, Ho ˆ pital Pitie ´ -Salpe ˆ trie ` re, Service de Rhumatologie, F-75013, Paris, France 8 Ho ˆ pital Charles-Foix, AP-HP, Service de Ge ´ riatrie, F-94205, Ivry sur Seine, France 9 Centre des Cordeliers, INSERM UMR-S 872, F-75006, Paris, France Summary Aging is generally associated with an increased predisposi- tion 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 situ- ation, we conducted the first extensive phenotypic and functional analysis of NK cells from healthy subjects, com- paring NK cells derived from newborn (cord blood), mid- dle-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 immatu- rity, 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. Key words: NK cells; Cord blood; Elderly; CD94 / NKG2A; Interferon gamma; cytotoxicity. Introduction Aging is a natural postmaturational process associated with increased mortality and morbidity from infectious diseases and cancer, attributable at least in part to defects in immunity (Miller, 1996; Hakim et al., 2004; Pawelec & Larbi, 2008). The complex process of immunosenescence affects both the innate and adaptive arms of the immune system. It has been linked to various factors, including thymic involution, the accumulation of memory T cells, which leads to contraction of the T-cell reper- toire, and a decline in B-cell production, reflecting defective humoral immunity (Aw et al., 2007; Hakim & Gress, 2007). At the same time, a variety of evidence indicates that aging exerts significant effects specifically on the innate immune system. Sev- eral alterations in the role of natural-killer (NK) cells have been described: both the number of cells and their functions change as people age (Solana et al., 1999; Plackett et al., 2004). Other studies, however, report that aging does not significantly affect NK cytotoxicity (Min et al., 2005; DelaRosa et al., 2006; Solana et al., 2006). The discrepant findings about the effects of age seem due mainly to the different selection criteria for the elderly populations studied; protocols with strict selection criteria that exclude individuals with infections, inflammation or cancer and focus on very healthy older people report the preservation of NK cell cytotoxicity (Mocchegiani & Malavolta, 2004). NK cells are the first line of defense against infections and developing malignancies. These cells are heterogeneous and differ in their proliferative potential, homing characteristics, functional capacities, and responses to different cytokines. They can be divided into two major subsets based on their rela- tive density of CD56 surface expression. Peripheral blood NK cells are comprised of around 10% CD56 brigh and 90% CD56 dim NK cell subsets, which are relatively distinct (Caligiuri, 2008); upon activation, CD56 bright NK cells proliferate, and pro- duce a wide range of cytokines (e.g. IFN-c, TNF-b, and IL-10) and chemokines (e.g. MIP-1a and RANTES) but display minimal cytotoxicity activity; in contrast, CD56 dim NK cells have little proliferation, produce relatively lower amounts of cytokines, and are highly cytotoxic (Freud & Caligiuri, 2006). Recent experimental evidences have demonstrated that NK develop- ment proceeds from a CD56 bright to CD56 dim phenotype (Chan et al., 2007; Romagnani et al., 2007; Yu et al., 2009). As our Correspondence Dr Vincent Vieillard, INSERM UMR-S 945, Laboratoire d’Immunologie Cellulaire et Tissulaire, Ho ˆpital Pitie ´-Salpe ˆtrie `re, Paris, France. Tel.: +33 142177524; fax: +33 142177490; e-mail: vincent.vieillard@upmc.fr Accepted for publication 19 April 2010 ª 2010 The Authors Journal compilation ª Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland 2010 527 Aging Cell (2010) 9, pp527–535 Doi: 10.1111/j.1474-9726.2010.00584.x Aging Cell