Cytotoxic Cells
T lymphocytes CD8+ and NK are essential to control viral infections due to their cytotoxic effect. These cells become activated after recognizing antigens attached to molecules of MHC-I presented by infected cells, which usually leads to the death of the infected cell by effector mechanisms (163).
Kamiya et al. (194) demonstrated that SARS-CoV-2 infection in humans dramatically reduces the total CD8+ and NK cell count, especially in patients who have developed more severe disease. The inhibition of these cells was characterized by an increase in the expression of NK inhibitory receptor CD94/NK group 2 member A (NKG2A), a type C lectin receptor of cytotoxic cells that acts as a potent suppressor when binding to minimally polymorphic MHC-I that present peptide sequences of other MHC-I molecules, inducing an inhibitory signal through two receptors with tyrosine-based inhibition motifs that suppress cytokine secretion and cytotoxic activity.
In patients who recovered from COVID-19, CD8+ and NK cell counts and the reduction in NKG2A expression were restored, suggesting that the inhibition of these cells is a result of SARS-CoV-2-mediated immunomodulation (10). Corroborating these data, it has been reported that other viral infections also manage to increase the expression of NKG2A in NK cells as a way to escape from the immune system (195).
SARS-CoV-2 studies involving CD8+ T cells have shown exhaustion of the effector capacity of these cells over time by the reduction of granzyme B, perforins, and lysosome-associated membrane protein 1, also known as LAMP-1 or CD107a, described as a marker of cytotoxic cells’ degranulation and an important parameter to assess the activity of these cells. CD8+ T cells from COVID-19 patients have a very marked activation phenotype with an increase in CD69, CD38, CD137, and CD44, especially in critically ill patients. However, despite presenting an increase in these activation molecules, these cells also have enhanced cell exhaustion proteins, such as PD1, Tim3, CTLA-4, and TIGIT, especially in more critically ill patients (9, 154, 170).
TIGIT receptor, present in T and NK cells, can bind to dendritic cell CD155 receptors and induce an increased expression of IL-10 and reduce IL-12, in addition to inhibiting T cell activation and blocking cytotoxicity of NK cells (196). The use of specific blockers for these receptors, such as anti-PD1 and anti-TIGIT, has helped in the recovery of the function of these cells. Therefore, it is logical to assume that specific NKG2A blockers could be an important tool to assist in the treatment of SARS-CoV-2 infections, restoring the functionality of cytotoxic cells (10, 195).
Together, these data described the increase in activation markers and cellular exhaustion, in addition to the reduction in functionality markers indicating that, like CD4+ T lymphocytes, these cells were probably hyperactivated right at the beginning of the infection, collaborating with the generation of a cytokine storm, until they became exhausted and lost their functional capacity, causing reduction of antigen-specific response and loss of its antiviral effects ( Figure 2 ).
Figure 2  Immune response in COVID-19 stages. SARS-CoV-2 infection is divided into three general phases. In the first one, called viremia, the virus spreads through the body and there is excessive activation of immune cells with exacerbated production of inflammatory mediators, such as IFN-γ, IL-2, and TNF-α, triggering cytokine storms and immune impairment. The second (acute) phase, characterized by the appearance of COVID-19 symptoms, presents a profile of immune cells still hyperactivated, but with the presence of cell exhaustion markers, such as Tim3, PD1, TIGIT, and NKG2A, in addition to losing the functional capacity of producign IFN, IL-2, and TNF-α. In this period there is still the appearance of CD14+ CD16+ hyperinflammatory monocytes, with a high production capacity of TNF-α, IL-1β, and IL-6, which will migrate to the lungs, contributing to the pathogenesis of respiratory failure and maintaining the cytokine storm. The lethargic state of the immune system in the early stages of infection may be related to the delay in the generation of a humoral response. In the third, or convalescence, phase, the individual can evolve in two opposite directions, recovery or clinical worsening/death. In recovery, cells of lymphoid origin recover their effector function and lose markers of exhaustion, while IgG levels improve. On the other hand, in patients with clinical worsening, this status of immune anergy continues.