The newborn human NK cell repertoire is phenotypically formed but functionally reduced

Abstract

Background Infection is a leading cause of death worldwide in babies under 1 month of age. Better vaccines and therapeutics are desperately needed for this vulnerable population. Methods Because newborns rely heavily on the innate immune system, we evaluated cell phenotype and function of some of the earliest cellular responders during infection, natural killer (NK) cells. We used mass cytometry to provide a comprehensive comparison of NK cells from umbilical cord blood and adult peripheral blood. Results In unsupervised analyses, including viSNE and principal component analysis, the structure of the cord blood and adult NK cell repertoires are highly similar, distinguishable mainly by maturity-related markers expressed on rare subpopulations of cells. However, in functional analyses, cord blood NK cells show reduced degranulation and cytokine production following target recognition, as well as antibody-dependent cell-mediated cytotoxicity and apoptosis induction in targets. Conclusions These findings show that the structure of the NK cell repertoire is intact at birth, suggesting great potential for vaccine and therapeutic strategies targeting this cell population.

The Broad Spectrum of Human Natural Killer Cell Diversity

“…Interestingly, newborn NK cell populations have relatively low diversity indices compared to those observed in adults despite the absence of any major age-related differences in NK cell repertoire structural components (e.g. phenotypically defined cNK cell subsets such as CD56 bright CD16 lo/− and CD56 dim CD16 + ) (Strauss-Albee et al, 2017). Taken together, these data indicate that genetics largely influences the expression patterns of inhibitory receptors including inhibitory MHC class I-binding receptors, whereas environmental exposures such as infection or cancer can have a substantial impact on increasing NK cell population diversity due to changes in activating receptor expression (Beziat et al, 2013).…”

“…Given that many stage 5 and stage 6 CD56 dim cNK cells in PB lack CD94/NKG2A expression and instead express different KIR isoforms and variable amounts of CD94/NKG2C, this implies that as a group cNK cells start out uniform in their MHC class I-binding receptor expression profile (i.e. CD94/NKG2A + KIR − CD94/NKG2C − ) and then at some point they diversify to yield NK cell repertoires with the remarkably high degree of heterogeneity detected in the PB of both healthy newborns and adults (Figure 1) (Strauss-Albee et al, 2017). Thus NK cell population diversity is likely a function of developmental stage (Bjorkstrom et al, 2010; Strauss-Albee et al, 2015).…”

Diversification of human NK cells: Lessons from deep profiling

“…First, NK cell diversity increases with age. Although differences in the structure of the human NK cell repertoire between cord blood and adult peripheral blood are largely limited to maturity-related markers like CD57 and NKG2A [194], NK cell diversity is higher in adult peripheral blood than in cord blood [188]. NK cell diversification with age could be a physiologic process, or represent the accumulation of diversity induced by exposures to new pathogens.…”

The road ahead: Implementing mass cytometry in clinical studies, one cell at a time

“…We highlight six studies that illustrate recent progress. The manuscripts by Yao et al , Corneau et al , and Strauss‐Albee et al emphasize the utility of mass cytometry for identifying cell subsets that capture patient‐specific disease attributes in the fields of pulmonology, neonatology, and virology. The studies by Abraham et al and Vendrame et al apply visualization and statistical tools in novel combinations to interpret high‐dimensional data, while the manuscript by Leelatian et al describes a standardized protocol to derive isolated cancer cells from solid tissue for analysis by mass cytometry.…”

“…Strauss‐Albee et al focus on the deep immune profiling of umbilical cord blood samples to better define the natural killer (NK) cell repertoire and functional capacity of newborns. The authors provide a comprehensive overview of neonatal NK cell subsets and their functional attributes.…”