Low Circulating Natural Killer Cell Counts are Associated With Severe Disease in Patients With Common Variable Immunodeficiency

• CVID patients with low NK cell counts present increased rates of severe bacterial infections and granuloma.
• Mortality appears to be especially high in CVID patients with both severe CD4+ T cell and NK cell deficiency.
• NK cells could have non-redundant immune functions in patients with non-optimal adaptive immune response.Forty years after their discovery, the functions of Natural Killer (NK) cells in natura remain poorly understood. Association studies linking clinical symptoms and defects in NK cell numbers or function are exceptional and poorly described in large cohorts of human patients. Our study analyzes the correlation between NK cell lymphopenia and clinical events in a large cohort of immunocompromised patients. We report the unexpected findings that severe invasive bacterial infections, especially bacteremia episodes, and non-infectious complications, especially granulomatous complications, are more frequent in common variable immunodeficiency patients with severe NK cell deficiency. These findings in natura highlights that NK cells may play a pivotal role in immunity in immunocompromised individuals, when the adaptive immune system is not optimal.

Natural Killer (NK) cells have been shown to exert antiviral and antitumoural activities. Nevertheless most available data are derived from mouse models and functions of these cells in human remain unclear. To evaluate the impact of low circulating NK cell counts and to provide some clues to the role of NK cells in natural conditions, we studied a large cohort of patients with common variable immunodeficiency (CVID) included in a multicenter cohort of patients with primary hypogammaglobulinaemia. Patients were classified into three groups on the basis of their NK cell counts: severe and mild NK cell lymphopenia (< 50 and 50–99 × 106/L respectively), and normal NK cell counts (> 100 × 106/L). Clinical events were analyzed and compared between these three groups of patients. During study period, 457 CVID patients were included: 99 (21.7%) with severe NK cell lymphopenia, 118 (25.8%) with mild NK cell lymphopenia and 240 (52.5%) with normal NK cell counts. Non-infectious complications (57% vs. 36% and 35%), and, particularly, granulomatous complications (25.3% vs. 13.6% and 8.8%), were more frequent in patients with severe NK cell lymphopenia than in other groups. Invasive infections (68.7% vs. 60.2% and 48.8%), including bacteraemia (22.2% vs. 5.9% and 8.3%) and infectious pneumonia (63.6% vs. 59.3% and 44.2%), were also more frequent in this population. However, no difference was observed for viral infections and neoplasms. Low circulating NK cell counts are associated with more severe phenotypes of CVID, which may indicate a protective role of these immune cells against severe bacterial infections and other complications and non-redundant immune functions when the adaptive immune response is not optimal.