Meta-analysis of the CD56-negative NK cell subset indicates altered functional responses and unique KIR regulation

Abstract

Abstract Chronic infections such as HIV-1, HCV, and some herpesviruses, expand a subset of NK cells that lack CD56 expression (CD56neg) and are less responsive to HLA-negative targets than CD56+CD16+ (CD56dim) cells. The 39 research papers that have reported on CD56neg NK cells have considered that this subset comprises anergic, dysfunctional or adaptive NK cells. Our objective was to assess these possibilities through meta-analysis of these papers, with inclusion of new data extracted from openly deposited CyTOF datasets (n=7). Data on CD56neg NK cells was extracted from papers. CyTOF datasets were downloaded and markers expressed by CD56neg cells identified. Meta-analysis was undertaken following the Cochrane guidelines using Random Effect Model assuming study variability. We found through analysis of “healthy” control groups (n=30) that the CD56neg subset represents 5.42% of peripheral blood NK cells, and confirmed that HIV-1 infection expands this population by 9.00%. Four studies presenting comparable functional data report decreased IFNγ and CD107a CD56neg cell responses to HLA-lacking targets compared to CD56dim cells (−5.99% and −4.24% respectively). Comparison to CD56dim marker expression showed no difference in Ki67 implying CD56neg cells are not anergic. The CD56neg subset also has a decreased proportion of CD57+NKG2C+ cells so are not adaptive NK cells. Lower KIR expression and range of KIR combinations were seen in CD56neg cells indicating their reduced responsiveness is linked to altered KIR:HLA signalling capacity. The expansion of this subset may be due to disrupted HLA expression induced by chronic viral infections, or may be an adaptation to long-term infection to mediate ongoing activation of the NK compartment.