Natural killer (NK) cells are an important component of innate immune responses to infectious diseases. They mediate protection by being able to rapidly lyse infected cells and produce cytokines (primarily interferon-γ) that shape innate and adaptive immune responses. This review summarizes current knowledge on the phenotype and functional abilities of NK cells from healthy newborns/infants and on NK cell responses against viral, bacterial and protozoan infections in early life. Interestingly, NK cell blood counts are higher in newborns than in adults but they do not display striking differences in phenotype, except for an increased frequency of expression of the inhibitory CD94/NKG2A receptor. They display some inherent functional defects, mainly a lower cytolytic capacity that may contribute to the immaturity of the neonatal immune system. Changes in circulating levels of NK cells observed during pediatric infections and the ability of NK cells from newborns and children to produce interferon-γ at the encounter with pathogens indicate that NK cells participate in the immune response to infectious diseases in early life. Unfortunately, information is currently insufficient to assess whether these NK cell responses really contribute to control infections, either vertically transmitted or acquired in infancy.

We previously reported that foetuses congenitally infected with Trypanosoma cruzi, the agent of Chagas disease, mount an adult-like parasite-specific CD8+ T-cell response, producing IFN-g, and present an altered NK cell phenotype, possibly reflecting a post-activation state supported by the ability of the parasite to trigger IFN-g synthesis by NK cells in vitro. We here extended our knowledge on NK cell activation by the parasite. We compared the ability of T. cruzi to activate cord blood and adult NK cells from healthy individuals. Twenty-four hours co-culture of cord blood mononuclear cells with T. cruzi trypomastigotes and IL-15 induced high accumulation of IFN-g transcripts and IFN-g release. TNF-a, but not IL-10, was also produced. This was associated with up-regulation of CD69 and CD54, and down-regulation of CD62L on NK cells. The CD56bright NK cell subset was the major IFN-g responding subset (up to 70% IFN-g-positive cells), while CD56dim NK cells produced IFN-g to a lesser extent. The response points to a synergy between parasites and IL-15. The neonatal response, observed in all newborns, remained however slightly inferior to that of adults. Activation of IL-15-sensitized cord blood NK cells by the parasite required contacts with live/intact parasites. In addition, it depended on the engagement of TLR-2 and 4 and involved IL-12 and cross-talk with monocytes but not with myeloid dendritic cells, as shown by the use of neutralizing antibodies and cell depletion. This work highlights the ability of T. cruzi to trigger a robust IFN-g response by IL-15-sensitized human neonatal NK cells and the important role of monocytes in it, which might perhaps partially compensate for the neonatal defects of DCs. It suggests that monocyte- and IL-12- dependent IFN-g release by NK cells is a potentially important innate immune response pathway allowing T. cruzi to favour a type 1 immune response in neonates.

Early interferon-gamma (IFN-γ) release by innate cells is critical to direct type 1 immune response able to control intracellular pathogens like Trypanosoma cruzi. Although CD56bright natural killer (NK) cells are reported to be potent early IFN-γ producers, other CD56+ cells like CD56dim NK cells and NK-like T cells have recently been shown to also release IFN-γ. We have here studied the contribution of each CD56+ lymphocyte populations in early IFN-γ production in both adults and neonates. On this purpose, we analysed the kinetics of IFN-γ production by RT-PCR, ELISA and flow cytometry from 2 h onwards after T. cruzi and IL-15 stimulation and sought for the responding CD56+ cells. CD56bright and CD56dimCD16− NK cells were the more potent IFN-γ early producers in response to IL-15 and parasites in adults and neonates. In both age groups, the majority of IFN-γ producing cells were NK cells. However, on the contrary to neonates, CD3+CD56+ NK-like T cells and CD3+CD56− ‘classical’ T cells also contributed to early IFN-γ production in adults. Altogether, our results support that whereas NK cells responded almost similarly in neonates and adults, cord blood innate CD56+ and CD56− T cells displayed major quantitative and qualitative defects that could contribute to the well-known neonatal immune immaturity.