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 NKG2A−KIR+LIR-1+CD57+CD56dim NK cell subset when derived from individuals previously exposed to pathogens, such as human cytomegalovirus (HCMV), may contain “memory-like” NK cells. These cells are generally characterized by an upregulation of the activating receptor CD94/NKG2C and a downregulation 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 antitumor and antiviral immune responses, longevity, as well as given epigenetic modifications. Interestingly, unknown cofactors associated with 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 antitumor NK cell activity that can be partially restored by antibody-mediated disruption of PD-1/PD-L interaction.
Highlights
In physiological conditions, human peripheral blood NK cells include different cell subsets corresponding to different stages of NK cell differentiation
The same NK cell subsets are characterized by distinct homing properties due to the different surface expression of chemokine receptors: CD56dim NK cells, expressing CXCR1, CX3CR1, and ChemR23, preferentially migrate to inflamed peripheral tissues [5, 6], whereas CD56bright NK cells, thanks to their CCR7 and CD62L expression, preferentially migrate to secondary lymphoid organs (SLOs) [6]
It cannot be excluded that programmed death-1 (PD-1) may represent an inhibitory checkpoint expressed on NK cells in various cancers of different histotype and that this inhibitory receptor may be involved in the impaired antitumor NK cell responses by these patients. It should be stressed/emphasized that, while, in conventional NK cells, the effector function against tumors is primarily regulated by the interactions between HLA-class I-specific inhibitory receptors (KIR and CD94/NKG2A) and HLA-class I molecules, in the case of PD-1+ NK cells, the simultaneous expression of PD-1 together with given inhibitory HLA-specific receptors may provide an additional level of suppression of NK cell-mediated antitumor responses
Summary
Human peripheral blood NK cells include different cell subsets corresponding to different stages of NK cell differentiation. This HCMV-induced NKG2C+CD57+ NK cell subset displays a highly differentiated surface phenotype, CD56dimCD16brightLIR-1+KIR+NKG2A−, and is characterized by the expression of self KIRs [33].
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