In both cases, CD161 expression levels appeared lower in NK cells from individuals with symptomatic HCMV infection, an effect that was not perceived when groups were compared (Fig. 1). The NKR distribution pattern associated to HCMV infection in T lymphocytes resembled only partially that observed in NK cells (Fig. 2). Overall, the absolute numbers of NKR+ T cells were increased in HCMV+ children, particularly in the congenital symptomatic group. In fact, the proportions of

NKG2C+, LILRB1+, and CD161+ T cells were significantly higher in congenitally infected than in noninfected children. In addition, NKG2A+ T cells appeared also higher in children with congenital symptomatic infection, at variance with the reduced proportions of NKG2A+ NK cells in the same group. Altogether, these results point Raf inhibitor out that marked changes in NKR distribution, particularly an increase of NKG2C+ and LILRB1+ NK cells, are associated with congenital symptomatic HCMV infection. The putative implications of the NKG2C deletion on the response to HCMV infection are uncertain. On that basis, a genotypic analysis of NKG2C was conducted in children with symptomatic (n = 15) and asymptomatic (n = 11) congenital infection, as well

as in a control group including children with postnatal infection (n Roscovitine concentration = 11) and noninfected (n = 19). The homozygous NKG2C deletion was found in a single uninfected control individual. In addition, no significant differences were found between the frequencies 3-mercaptopyruvate sulfurtransferase of the heterozygous NKG2C+/− genotype detected in uninfected controls and children with congenital infection (42.1% versus 34.6%; p = 0.61). Altogether these results argue against a direct relation of the NKG2C deletion with the incidence of congenital HCMV infection in newborns. In line with previous reports [26, 27, 32], individual differences in NKG2C surface staining intensity were noticed (Supporting Information Fig. 1). The NKG2Cbright/intermediate expression pattern was generally

associated to HCMV infection, whereas all noninfected and ∼43% of infected children displayed a predominant NKG2Cdim phenotype. The proportions of NKG2C+ cells correlated significantly (r = 0.74; p < 0.001) with the KLR surface expression levels (MFI). The possibility that NKG2C copy number might influence the expansion of NKG2C+ cells and/or the expression levels of the receptor was addressed. To this end, the proportions and absolute numbers of NK cells bearing NKG2C, as well as its surface staining intensity, were compared after stratification for HCMV infection and the NKG2C genotype. As expected, increased proportions of NKG2C+ NK cells and higher surface levels of the KLR were detected in HCMV-positive children (Table 3); though less marked, a significant association of both parameters with the NKG2C genotype was also noticed.