Points HCMV infection in early life is associated with rapid phenotypic

Points HCMV infection in early life is associated with rapid phenotypic and functional differentiation of NK cells. CD56bright NK cells express cytokine receptors and produce interferon (IFN)-γ in response to cytokines. In contrast CD56dim cells express FcγRIII(CD16); express varying levels of CD94/NKG2A KIR NCRs and perforin; retain their ability to secrete AMD 3465 Hexahydrobromide IFN-γ; and have higher cytotoxic capacity.3 Heterogeneity within the CD56dim subset is associated with acquisition of CD57.2 4 5 CD56dimCD57? NK cells are phenotypically and functionally similar to CD56bright cells whereas CD56dimCD57+ cells produce little IFN-γ and have shorter telomeres and lower proliferative capacity 5 6 but degranulate extensively after crosslinking of CD16.2 5 Acquisition AMD 3465 Hexahydrobromide of CD57 is associated with onset of expression of NKG2C although the codependence of these events and their implications for function are not understood.7 8 Although the external drivers of NK cell differentiation are incompletely understood inflammation associated with infection or loss of immune homeostasis plays a key role.9 This view is supported by evidence that the late differentiation marker CD57 can be induced on NK cells by high concentrations of IL-2 5 that NKG2C+ NK cells can be expanded by coculture with human cytomegalovirus (HCMV)-infected fibroblasts 10 that HCMV-seropositive individuals have increased frequencies of NKG2C+ NK cells 10 and that there is rapid expansion of CD57+NKG2Chi NK cells during acute HCMV infection14 and in individuals infected with Epstein Barr virus (EBV) 7 hantavirus 15 hepatitis viruses 16 and chikungunya virus.17 Among Caucasians NK cell maturation is highly age-dependent. Marked phenotypic and functional differences are observed between NK populations in cord blood in young children in adults and in elderly individuals.18-22 Young children have higher frequencies of CD56brightCD16? and NKG2A+NKG2C? NK cells compared with adults and younger adults have higher frequencies of these cells compared with the elderly.18-22 Moreover NCR+ and NKG2D+ NK cells decrease in frequency with increasing age concomitant with loss of CD62L and acquisition of CD57.2 4 18 22 NK cell cytokine production decreases with increasing age but cytotoxic responses are conserved.9 20 23 There is however a lack of data from older children and teenagers. The extent to AMD 3465 Hexahydrobromide which NK cell differentiation is explained by either aging per se or by cumulative exposure to infection is unclear. Among allogeneic hematopoietic stem cell transplant recipients the first wave of repopulating NK cells comprises predominantly CD56bright or CD56dimCD94+cells; KIR+ and CD57+ cells can take up to 1 1 year to emerge.2 24 However among patients who reactivate HCMV after transplantation NKG2C+CD57+ NK cells can be detected within 3 months and the host’s pretransplantation repertoire is fully reconstituted within 6 months suggesting that exposure to infection is a significant determinant of NK cell maturation rates.24-26 Together these data suggest that age-related changes in NK cell phenotype and function may be modified by the infection status of the host and that rates of change across populations may depend on the prevalence of particular infections. If so the prevalence of infections such as HCMV may have far-reaching implications for risk for other infections cancers or autoimmune disease. To begin to address this important AMD 3465 Hexahydrobromide aspect of NK cell biology we have characterized NK cell phenotype and function in an African population that is itself Rock2 characterized by a high burden of infectious disease including near-universal HCMV infection. Materials and methods Study subjects This study was approved by the ethical review committees of the Gambia Government/Medical Research Council and the London AMD 3465 Hexahydrobromide School of Hygiene and Tropical Medicine. Participants were recruited from the villages of Keneba Manduar and Kantong Kunda in the West Kiang district The Gambia. After fully informed consent was obtained in accordance with the Declaration of Helsinki including parental/guardian consent for minors venous blood samples were collected from 191 individuals aged 1 to 49 years..