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Natural killer cells in hepatitis C virus recurrence following liver transplantation: what role do they play?

Natural killer (NK) cells are a type of lympho cyte that constitute a major component of the innate immune system [1]. NK cells play an important role in the rejection of tumors and cells infected by viruses through direct or indirect cytolytic mechanisms. The target cells die by apoptosis or necrosis due to the release of two proteins: perforin and granzyme. In this process, proinflammatory cytokines, such as IFN-g, and cytoplasmic granules are also released [2]. In humans, NK cells express killer cell immunoglobulin-like receptors (KIRs) on their surface, which specifically recognize the HLA Class I antigens of the major histo compatibility complex present on target cells. The effector functions of NK cells are influenced by inhibitory receptors for self-HLA Class I ligands HLA-A, -B and -C, with HLA-C and Bw4 being the predominant ligands for most KIR receptors [3]. The dimorphism in amino acids present in the a 1 helix of the HLA-C molecules is characterized by Ser77/Asn80 and Asn77/Lys80 that define distinct allotypes of HLA-C (C1 and C2, respectively). The alleles encoding the C1 epitope include HLA-C*01, *03, *07 and *08, which interact with the KIR receptors 2DL2/3 and 2DS2. The alleles encoding the C2 epitope include HLA-C*02, *04, *05 and *06, which interact with the 2DL1 and 2DS1 receptors [4,5]. The KIRs 3DL1 and 3DS1 interact with HLA-Bw4, and KIR 3DL2 recognizes HLA-A3 and -A11 [6]. Several studies have pointed out that hepatitis C virus (HCV) persistence might be associated with a defective NK cell response [7–10] and that therapy with IFN would re-establish NK cell activity [11]. In the last few years, several studies highlighting the possible role of KIR receptors and ligands in persistence of HCV infection have been published in the scientific literature [12–14]. In a study that appeared in Science in 2004, Khakoo et al. demonstrated that KIR2DL3 and homozygosity for its ligand C1 are associated with resolving HCV infection in patients with a low viral load [12]. In another paper, the same group postulated that different genotypes confer either susceptibility or resistance to infectious diseases [13]. Lopez Vazquez et al. identified a protective effect of HLA-Bw4I80 receptor 3DS1 against the development of hepatocellular carcinoma [14]. Paladino et al. have shown that NK receptors are associated with the elimination of HCV. In particular, they found that the frequency of the KIR2DL3 gene was significantly higher in HCV RNA-positive patients with serum transaminase levels above the normal limit [15]. In addition, they found that lower KIR2DL2 and 2DS2 frequencies were associated with increased frequencies of KIR2DS5 in subjects who cleared the virus. In contrast to the studies described previously, Rauch et al. did not find any implication of KIR genes in resolving HCV infection. However, these results might be biased owing to a low sample size and/or the lack of information on patient viral load [16]. Alejandro Espadas de Arias Researcher, Department of Regenerative Medicine, Organ and Tissue Transplantation Immunology, Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena – Via Francesco Sforza 35, 20122 Milan, Italy alejandro.espadas@policlinico.mi.it