Influence of congenital human cytomegalovirus infection and the NKG2C genotype on NK‐cell subset distribution in children

Abstract

Human cytomegalovirus (HCMV) has been reported to reshape the NK-cell receptor (NKR) distribution, promoting an expansion of CD94/NKG2C + NK and T cells. The role of NK cells in congenital HCMV infection is ill-defined. Here we studied the expression of NKR (i.e., NKG2C, NKG2A, LILRB1, CD161) and the frequency of the NKG2C gene deletion in children with past congenital infection, both symptomatic (n = 15) and asymptomatic (n = 11), including as controls children with postnatal infection (n = 11) and noninfected (n = 20). The expansion of NKG2C + NK cells in HCMV-infected individuals appeared particularly marked and was associated with an increased number of LILRB1 + NK cells in cases with symptomatic congenital infection. Increased numbers of NKG2C + , NKG2A + , and CD161 + T cells were also associated to HCMV infection. The NKG2C deletion frequency was comparable in children with congenital HCMV infection and controls. Remarkably, the homozygous NKG2C +/+ genotype appeared associated with increased absolute numbers of NKG2C + NK cells. Moreover, HCMV-infected NKG2C +/+ children displayed higher absolute numbers of NKG2A + and total NK cells than NKG2C +/− individuals. Our study provides novel insights on the impact of HCMV infection on the homeostasis of the NK-cell compartment in children, revealing a modulatory influence of NKG2C copy number. Eur. J. Immunol. 2012. 42: 3256-3266 Immunity to infection 3257 lifelong latent state, occasionally undergoing reactivation, but may have a pathogenic role in immunodeficient and immunosuppressed patients [1][2][3]. Moreover, HCMV has been associated with atherosclerosis, lymphoproliferative disorders, and glioblastoma, as well as with an accelerated immunosenescence and a shorter lifespan [4][5][6][7]. Vertical transmission of HCMV during pregnancy is considered the most common cause of congenital infection worldwide, affecting ∼0.2-2% of infants and potentially causing fetal lesions [8][9][10]. Though most infected newborns are asymptomatic, ∼10% display a variety of clinical disorders [8,11] potentially leading to important sequelae such as mental retardation and deafness. The type of maternal infection (i.e., primary versus reactivation/reinfection) conditions the risk of congenital infection and the pregnancy stage at which transmission occurs is related to clinical severity [12][13][14][15][16]. Maternal antibodies with neutralizing activity are transferred to the fetus predominantly during the third trimester of gestation and may prevent congenital CMV disease [17]. Among other factors, fetal immune immaturity may determine the outcome of congenital infection [18,19]. An effective defense against HCMV requires the participation of T and NK cells, and the virus has developed different immune evasion strategies [20]. Patients with congenital HCMV infection have been shown to display mature CD8 + T-cell responses [21,22], and an expansion and differentiation of a specific TcR γδ + cell subset has been recently reported [23]. In contrast, information on the role of...

Natural killer cell memory in infection, inflammation and cancer

“…Additionally, TIM3 (also known as HAVCR2) 92,93 , which inhibits by a so far undefined mechanism, and the E3 ubiquitin ligase CBL-B, which inactivates the TAM family of receptors (TYRO3, AXL and MER) 94 , have also been shown to inhibit the activation of NK cells. There is emerging evidence that the formation of NK cell memory for HCMV can also occur in individuals carrying a homozygous null allele of KLRC2, which encodes NKG2C 41 . So far, the receptors driving the NK cell response against HCMV in the absence of CD94-NKG2C are poorly understood.…”

Relationship of NKG2C Copy Number with the Distribution of Distinct Cytomegalovirus-Induced Adaptive NK Cell Subsets

“…Based on the reported relation of the NKG2C genotype with the magnitude of NKG2C + NK cell expansion in HCMV + subjects (6,14), the possible influence of the NKG2C copy number on FcRg 2 NK cell numbers was assessed. Phenotypic data from HCMV + individuals with an NKG2C bright NK cell profile (n = 26) were stratified according to their NKG2C genotype.…”

“…Studies in congenital or perinatal HCMV infection, as well as in transplant recipients, indicate that the expansion of NKG2C bright NK cells may be detected relatively early following HCMV infection and tends to remain fairly stable over time (10)(11)(12)(13)(14)(15). The strict association between NKG2C bright NK cells and HCMV seropositivity, even in the context of other viral infections (i.e., HIV, hepatitis C virus, EBV, Hantavirus, and Chikungunya virus) (4,(16)(17)(18)(19), supports the existence of an HCMV-specific condition promoting the persistent modification of the NK cell compartment homeostasis.…”

“…Yet, an active role for CD94/NKG2C is supported by in vitro data showing a preferential expansion of CD94/NKG2C + NK cells upon stimulation with virus-infected fibroblasts in a CD94- (20), NKG2C-, and HLA-E-dependent manner (21). Moreover, ∼5% of the population is homozygous for a deletion of the NKG2C gene (officially designated KLRC2), and NKG2C zygosity has been shown to influence NKG2C + NK cell numbers in steady state, as well as the receptor function in HCMV + subjects (6,14,22). The response of NKG2C + NK cells to HCMV resembles that of memory-like Ly49H + NK cells, which expand following recognition of the MHC-like m157 molecule in murine CMV-infected cells and confer an efficient defense against reinfection (23)(24)(25).…”

Antibody-Mediated Response of NKG2Cbright NK Cells against Human Cytomegalovirus

“…The development of HCMV-induced NKG2C bright NK cells is observed following the primary infection early in life, in intrauterusinfected newborns and upon HCMV reactivation in immunosuppressed hosts such as hematopoietic and solid organ transplant patients (20)(21)(22)(23). HCMV-induced NKG2C + NK cells resemble the Ly49H + NK cell subset in murine CMV infection, which, through specific recognition of the viral MHC-I-like m157 protein, contribute to viral clearance and persist in the circulation conferring protection to subsequent murine CMV exposures (24)(25)(26).…”