BioAcyl Corp

In December 2019, in Wuhan, China, came the first reports of pneumonia cases due to a coronavirus, the severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2), a novel strain related to SARS-CoV and Middle East respiratory syndrome–CoV, responsible for previous outbreaks. Disease related to SARS-CoV-2 (i.e., coronavirus disease 2019 [COVID-19]) can vary from mild disease to life-threatening acute respiratory distress syndrome (ARDS). ARDS is caused by a sustained and dysregulated immune response triggered in the lung after an initial insult, resulting in alteration of alveolar–capillary membrane permeability and tissue repair (Thompson et al., 2017). This pathological process leads to interstitial and alveolar edema that strongly impairs gas exchange. The cellular and molecular factors that are responsible for this aberrant and persistent inflammatory response are poorly understood (Matthay et al., 2019).

During severe SARS-CoV-2 infection, elevated proinflammatory cytokine levels (e.g., IL-6 and TNF-α) were associated with more severe cases, supporting an inflammatory hypothesis (Chen et al., 2020; Mehta et al., 2020; Qin et al., 2020). In addition, T cell lymphopenia has been correlated with disease severity, suggesting a role for these cells in the pathophysiology of severe COVID-19 (Chen et al., 2020; Qin et al., 2020). Besides classic adaptive CD4⁺ and CD8⁺ T cells, the T cell compartment comprises several lineages of cells endowed with both innate and adaptive properties that are referred to as unconventional T (uT) cells (Godfrey et al., 2015). This heterogeneous class of T cells comprises three main lineages, including mucosa-associated invariant T (MAIT), γδT, and invariant natural killer T (iNKT) cells. These cells recognize nonpeptide antigens, are not restricted to classic MHC, and have emerged as key players in mucosal immunity and inflammatory response (Crosby and Kronenberg, 2018; McCarthy and Eberl, 2018; Trottein and Paget, 2018; Toubal et al., 2019). Given their versatile functions, uT cells could be important actors in the context of SARS-CoV-2–driven ARDS. First, uT cells mainly populate mucosal tissues, including the lung, and have the ability to promptly produce substantial amounts of inflammatory cytokines such as IFN-γ and IL-17A, two key cytokines in the antimicrobial response at barrier sites. Moreover, uT cells can fine-tune the intensity and quality of the host immune response, shaping the magnitude of the adaptive response. Hence, they have been shown to contribute in anti-infective responses to viruses (Déchanet et al., 1999; Paget et al., 2011; Loh et al., 2016; van Wilgenburg et al., 2016) and bacteria (Bonneville, O’Brien and Born, 2010; Le Bourhis et al., 2010; Crosby and Kronenberg, 2016), especially during pneumonia (Trottein and Paget, 2018). They can also participate in the process of the resolution of inflammation, including tissue repair and regeneration (Nielsen, Witherden and Havran, 2017; Hinks et al., 2019; Lamichhane et al., 2019; Leng et al., 2019; Paget and Trottein, 2019), a critical step that is impaired during ARDS. Despite that, the contribution of uT cells in the pathophysiological process of SARS-CoV-2–driven ARDS has never been explored.

Here, we dynamically assessed the relative frequencies and functions of uT cells in biological fluids of 30 patients with severe COVID-19 who were admitted to the intensive care unit (ICU). Our analysis indicates that uT cells from severe COVID-19 patients display a phenotype of activated cells associated with changes in their cytokine profile. Importantly, activated uT cells populated the airways of patients displaying strong local inflammation. In addition, the activation status of blood uT cells on admission was predictive of the level of hypoxemia during the course of infection. Thus, we show here that severe COVID-19 influences the phenotype and function of uT cells. This should encourage further investigation to assess the precise functions of uT cells and their associated activation mechanisms of uT cells during SARS-CoV-2–driven ARDS.