Experimental Gerontology 39 (2004) 1223–1232

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of KIR diversity in immunosenecence and longevity within the Irish population

a,b,* a,b b c a,d D. Maxwell , Owen A. Ross , Martin D. Curran , I. Maeve Rea , Derek Middleton

bSchool of Biology and Biochemistry, Queens University of Belfast, 97 Lisburn Road, Northern Ireland, cDepartment of Geriatric Medicine, Queens University of Belfast, Northern Ireland, UK dSchool of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, UK

Received 23 March 2004; received in revised form 19 May 2004; accepted 26 May

Available online 19 June 2004

Abstract

Natural killer (NK) cells play a pivotal role in the innate immune response. During the ageing process, variations occur in NK cell number and function. The cytolytic activity of NK cells is controlled by an array of activating and inhibitory cell surface receptors, including the killer cell immunoglobulin-like receptors (KIRs). In the present study, genetic diversity of the KIR loci was analysed with respect to successful ageing in the Irish population. A PCR–SSOP KIR gene identification system was employed to determine the frequency of the named KIR genes/pseudogenes and KIR genotypes within a healthy aged cohort and young control group. Although, two KIR genes (2DS3, 2DL5) displayed an initial increased frequency in the aged group, the significance of this association was lost when repeated in a second cohort. In view of the lack of studies to date, investigating the role of the KIR gene system in healthy ageing, further analysis of KIR diversity is required to fully elucidate it’s role in respect to age-related disease and longevity.

Keywords: Natural killer cell; KIR; Polymorphism; Ageing; BELFAST

1. Introduction

Natural killer (NK) cells play a pivotal role in the innate immune response and an increase in the number of NK cells is observed in the healthy elderly due to expansion of the functionally mature NK cell subset (McNerlan et al., 1998; Solana et al., 1999). Accompanying the rise in NK cell number, a decrease in cytotoxic capacity occurs on a per cell basis and thus overall NK cell cytoxicity in the healthy aged is maintained at a level comparable to young controls (Di Lorenzo et al., 1999; Miyaji et al., 2000). Studies suggesting that impaired NK cell activity is associated with atherosclerosis and death due to infection in the elderly have also been reported (Bruunsgaard et al., 2001; Ogata et al., 2001). These findings support the hypothesis that a well- preserved NK cell activity is important for successful ageing

Deterioration of the immune system with age (immu- nosenescence) and the associated increased susceptibility of the elderly to infectious disease, cancer and autoimmune disorders, have led to extensive investigation of immune parameters in the aged (Pawelec and Solana, 1997; Franceschi et al., 2000a; Malaguarnera et al., 2001). Several studies have reported a decline in T cell number and function and a decrease in B cell number, which collectively would result in impaired cellular and humoral immune responses (reviewed by Ginaldi et al., 1999). Accompanying the decline in adaptive immune function, alterations in certain cells that mediate non-specific immunity are also observed.

Due to their role in the innate response, NK cells provide a ‘first line of defence’ against infectious agents and cancer (Malnati et al., 1993; Biron et al., 1999; Wu and Lanier, 2003), and are also thought to play a role in autoimmunity (Shi et al., 2000; Singal et al., 2000). NK cells mediate their immune function through the recognition and lysis of

* Corresponding author. Address: Northern Ireland Regional Histocompatibility and Immunogenetics Laboratory, Blood Transfusion Building, City Hospital, Belfast BT9 7TS, Northern Ireland, UK. Tel.: þ44-28-90263979; fax.: þ44-28-90263880.

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L.D. Maxwell et al. / Experimental Gerontology 39 (2004) 1223–1232

pf KIR2DL 7 KIR2DS KIR3DL KIR3DSKIR2DS1-5 KIR3DS1 KIR2DL1-3 KIR2DL4 KIR2DL5 KIR3DL1-3

Fig. 1. KIR are type I transmembrane glycoproteins belonging to the immunoglobulin superfamily. They possess a cytoplasmic tail, transmembrane domain, linker region and either two (KIR2D) or three (KIR3D) extracellular Ig-like domains (Salter et al., 1997; Marsh et al., 2002). The three extracellular domains are organised into a membrane distal, a middle and a membrane proximal domain that are known as the D0, D1 and D2 Ig-like domains, respectively (Middleton et al., 2002). Members of the KIR family also possess short (S) and long (L) forms of cytoplasmic tail. These arise as a result offrameshifts caused by insertions and/or deletions of 1–4 nucleotides within the exons that encode the transmembrane and cytoplasmic domains. KIRs with short cytoplasmic tails transmit activating signals via the interaction of a charged amino acid residue, within the transmembrane region, with DAP12, an adaptor molecule, which contains immunoreceptor tyrosine, based activation motifs (ITAMs) (Lanier et al., 1998). Long-tailed KIRs transduce inhibitory signals by virtue of the immunoreceptor tyrosine based inhibitory motifs (ITIMs) (I/VxYxxL/V) that are present in their cytoplasmic tails (Bruhns et al., 1999). KIR2DL4 contains signature sequences of both activating and inhibiory KIRs (Selvakumar et al., 1996).