NK cell dysfunction in severe COVID-19: TGF-β-induced downregulation of integrin beta-2 restricts NK cell cytotoxicity
Joana Barros‐Martins, Reinhold Förster, Berislav Bošnjak
Abstract
In a recent study published in Nature, Witkowski et al. reported that in patients with severe forms of coronavirus disease 2019 (COVID-19) deranged tumor growth factor-beta (TGF-) secretion counteracts interferon-alpha (IFN-)-induced activation of NK cells by decreasing expression of transcription factor T-bet. Consequently, NK cells fail to upregulate the adhesion molecule integrin beta-2 (-2), which impedes their attachment to and killing of SARS-CoV-2 infected cells. 1 Infection with severe acute respiratory syndrome coronavirus type-2 (SARS-CoV-2) results in divergent courses, ranging from asymptomatic infections to lethal COVID-19. Besides predisposing factors including various comorbidities, severe COVID-19 is also caused by misdirected, untimed, and/or hyper-activated immune responses. It is, therefore, crucial to characterize the role of individual leukocyte subsets in response to SARS-CoV-2 infection. NK cells, traditionally identified as CD3 -CD56 + leukocytes, contribute to the early antiviral response by eliminating virus-infected cells. Their role in SARS-CoV-2 infection is still poorly understood. Although NK cells accumulate in the lungs of patients early after COVID-19 onset, in severe COVID-19 patients they were shown to have impaired antiviral activity. 2,3 To determine the role of NK cells in protection against SARS-CoV-2, Witkowski et al. compared viral loads in COVID-19 patients with "normal" (> 40 NK/l) or "low" ( 40 NK/l) NK cell counts. 1 They found that viral loads declined slower in patients with lower blood NK cell counts, suggesting that NK cells contribute to early infection control by eliminating SARS-CoV-2 infected cells. To validate their findings, the authors established an in vitro model in which NK cells were cultured with SARS-CoV-2 infected cell lines. In this model, NK cells from healthy donors dose-dependently killed infected cells, while NK cells from hospitalized COVID-19 patients were strongly impaired in mediating their protective function.