We performed an analysis of innate immune responses in a group of in-patients affected by chronic neurological conditions who either were recovering from SARS-CoV-2 infection or were never infected by the virus, with a focus on NK cells. Results of phenotypic analyses showed that patients who were recovering from severe COVID-19 are characterized by a peculiar skewing in NK cell subpopulations. Thus, in these patients, CD56-CD16bright were increased whereas CD56dimCD16- and CD56dimCD16bright NK cells were reduced in comparison to patients who suffered from either mild or moderate COVID-19.
An expansion of CD56-CD16 bright NK cells was previously described only once as it was show to be present in viremic HIV-infected patients, but not in those individuals in whom antiretroviral therapy resulted in viremia suppression [18]. This NK cell subpopulation is characterized by a significantly lower cytolytic activity and a scarce ability to secrete cytokines [19]. The parallel observation that the CD56dimCD16 − and the CD56dimCD16bright NK cell subsets were reduced in patients who were recovering from severe COVID-19 corroborates the idea that NK cell-mediated immune responses are impaired in severe SARS-CoV-2 infection. Thus, CD56dimCD16 − cells are a population with a potent antiviral activity which is mediated both by a potent cytolytic activity and the production of high amounts of IFNγ [20, 21]. These cells were recently shown to be decreased in COVID-19 patients with a diagnosis of ARDS and who required mechanical ventilation [22].
CD56dimCD16bright NK cells, on the other hand, besides being characterized as well by a potent cytolytic activity, were also shown to be particularly apt at activating antibody- dependent cellular cytotoxicity (ADCC) in response to viruses, including influenza virus, herpes simplex virus type 1 and HCMV [23–25]. NK-mediated ADCC was recently suggested to contribute to viral control in COVID-19 patients, as antibodies elicited toward the SARS-CoV-2 S glycoprotein (S309- and S306) -transfected cells could efficiently trigger ADCC [26]. To summarize these results, thus, we observed that severe COVID-19 infection is associated with a peculiar NK subset profile characterized by the expansion of cells with low cytotoxic abilities and the reduction of those NK cells that mediate efficient antiviral effector mechanisms.
NK cells are activated following the interaction between HLA molecules and KIR activating and inhibitory receptors, and the net imbalance between these two families of qualitatively antagonist receptors dictates whether NK cell will or will not be activated. Analyses of KIR activating and inhibitory receptors on NK CD56dimCD16bright cells, the major representative subset in peripheral blood, showed that, whereas no differences could be seen in the expression the activating 2DS1, 2DS2 and 2DS4 receptors the percentage of NK cells expressing the inhibitory receptor 2DL1 was significantly increased in severe COVID-19 patients. The skewing towards a preferential expression of inhibitory NK cell-associated molecules in COVID-19 patients was further supported by results showing that ILT-2 expression, another inhibitory receptor, was augmented as well on NK cells of all COVID-19 patients. Our results also suggest that the presence of the inhibitory 2DL1complex, particularly when in association with the C2 protein (KIR2DL1-C2) is a risk factor toward more severe form of COVID-19 development.
An imbalance in the ratio of NK inhibitory and activating receptors is present in a number of diseases [27], and it was clarified that KIR/HLA interactions influences both susceptibility and protection towards infective diseases [28–32]. Within the scenario of infectious diseases, an increased expression of inhibitory NK cell receptor on the CD56-CD16 + NK cells was shown to be present in HIV-infected viremic patients and to result in the inhibition of CD16-induced cytotoxicity [18]. Notably, recent results showed that the density of 2DL1 is higher on NK cells of COVID-19 patients with a diagnosis of acute respiratory distress syndrome (ARDS) [14]. This result, thus, further supports the hypothesis that NK function is defective in patients who suffer from severe forms of SARS-CoV-2 infection within an extremely complex scenario of immune impairment that involves multiple cell types. In conclusion an altered distribution of NK subsets and a preferential expression of NK imbalance of inhibitory receptor is observed in convalescent COVID-19 patients and in particular in those who suffered from a more severe form of infection.
The limit of the study is the small number of patients. Ampler cohorts of individuals, possibly followed within a longitudinal study, will be needed to better understand the different mechanisms implemented by the virus to evade the immune system during infection and the immune defense strategies put into play to counter and eliminate the virus.