AUTHOR=Della Chiesa Mariella , Pesce Silvia , Muccio Letizia , Carlomagno Simona , Sivori Simona , Moretta Alessandro , Marcenaro Emanuela 

TITLE=Features of Memory-Like and PD-1+ Human NK Cell Subsets

JOURNAL=Frontiers in Immunology

VOLUME=Volume 7 - 2016

YEAR=2016

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2016.00351

DOI=10.3389/fimmu.2016.00351

ISSN=1664-3224

ABSTRACT=Human NK cells are distinguished into CD56brightCD16- cells and CD56dimCD16+ cells. These two   subsets are conventionally associated with differential functional outcomes and are heterogeneous with respect to the expression of KIR and CD94/NKG2 heterodimers that represent the two major types of HLA class I-specific receptors.  
Recent studies indicated that immature CD56bright NK cells, homogeneously expressing the inhibitory CD94/NKG2A receptor, are precursors of CD56dim NK cells that in turn during their process of differentiation lose expression of CD94/NKG2A, and subsequentially acquire inhibitory KIRs and LIR-1. The terminally differentiated phenotype of CD56dim cells is marked by the expression of the CD57 molecule that is associated with poor responsiveness to cytokine stimulation, but retained cytolytic capacity.
Remarkably, this CD56dimNKG2A-KIR+LIR-1+CD57+ NK cell subset when derived from individuals previously exposed to pathogens, such as HCMV, may contain "memory-like" NK cells. These cells are generally characterized by an up-regulation of the activating receptor CD94/NKG2C and a down-regulation of the inhibitory receptor Siglec-7. The “memory-like” NK cells are persistent over-time and display some hallmarks of adaptive immunity, i.e. clonal expansion, more effective anti-tumor and anti-viral immune responses, longevity as well as given epigenetic modifications. Interestingly, unknown co-factors associated to HCMV infection may induce the onset of a recently identified fully mature NK cell subset, characterized by marked downregulation of the activating receptors NKp30 and NKp46 and by the unexpected expression of the inhibitory PD-1 receptor. This phenotype correlates with an impaired anti-tumor NK cell activity that can be partially restored by antibody-mediated disruption of PD-1/PD-L interaction.