Cellular immune states in SARS-CoV-2-induced disease

Abstract

The general immune state plays important roles against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Cells of the immune system are encountering rapid changes during the acute phase of SARS-CoV-2-induced disease. Reduced fraction of functional CD8⁺ T cells, disrupted cross-talking between CD8⁺ T cells with dendritic cells (DCs), and impaired immunological T-cell memory, along with the higher presence of hyperactive neutrophils, high expansion of myeloid-derived suppressor cells (MDSCs) and non-classical monocytes, and attenuated cytotoxic capacity of natural killer (NK) cells, are all indicative of low efficient immunity against viral surge within the body. Immune state and responses from pro- or anti-inflammatory cells of the immune system to SARS-CoV-2 are discussed in this review. We also suggest some strategies to enhance the power of immune system against SARS-CoV-2-induced disease.

Keywords: CD8+ T cell; SARS-CoV-2; dendritic cell (DC); immunity; monocyte; myeloid-derived suppressor cell (MDSC); neutrophil; regulatory T cell (Treg).

Figure 1

Interactions among cells of the immune system in SARS-CoV-2-induced disease. SARS-CoV-2 antagonizes STAT1 phosphorylation, which is linked to the reduced immune activation in monocyte-derived dendritic cells (DCs). The impact of SARS-CoV-2 on DCs results in the production of autoantibodies against interferon (IFN)-1. Activation of CD8⁺ T cells is essential for virus clearance, and the activity of CD4⁺ T cells is important for the activation of CD8⁺ T cells and optimal antibody responses. IL-3 released from CD4⁺ and CD8⁺ T cells stimulates IFN-α, which is further linked to the higher fraction of plasmacytoid DCs (pDCs). The effector activity of T cells is suppressed by SARS-CoV-2 inducible effect on myeloid-derived suppressor cells (MDSCs) and further release of ILs 6 and 10 from the cells. IL-6 stimulatory effect on Notch4 expression from regulatory T cells (Tregs) contributed to severe lung inflammation via hampering release of amphiregulin. Granulocytic (G)-MDSCs also suppress the proliferation of T cells through the release of arginase-1 (ARG-1), which contributed to lyphocytopenia. ARG-1 activity and the resultant low L-arginine level contributed to platelet activation and thrombosis. In addition, MDSCs block IFN-γ production from T cells through releasing transforming growth factor (TGF)-β.

Figure 2

M1/M2 cellular states in SARS-CoV-2-induced disease. M1 macrophages are pro-inflammatory and are active during the early stage of viral entry, whereas M2 macrophages are anti-inflammatory that are active during late stages. Viral replication and fusion are high in M1 macrophages, whereas the rate of replication is low in M2 macrophages. Lower lysosomal pH favors more viral degradation in lysosomes of M2 macrophages. Therefore, M1 macrophages are more prone to viral load and lung infection. The expression of angiotensin-converting enzyme 2 (ACE2) on M2 macrophages is reduced by IL-13 released from T helper 2 (Th2) cells, which is indicative of a level of resistance among M2 macrophages. Th1 cells are induced by M1 macrophages. Th1 polarity with pro-cytolytic activity is also induced by severe SARS-CoV-2. A shift from M1- to M2-like phenotype is required for promoting resolution of inflammation.

Figure 3

Diverse functionality of CD8⁺ T cells and regulatory T cells (Tregs) in patients with SARS-CoV-2-induced disease. During the early-stage of the disease, the activity of CD8⁺ T cells is protective, whereas the cells are hyper-active and amplify inflammatory responses associated with cytokine storm and lung damage at late stage of the disease. Tregs have their own pros and cons during each disease stage. At early stage, Tregs dampen systemic inflammation, but they can hamper anti-viral defense systems. At late stage of the disease, Tregs protect body organs from inflammatory-related damages, but they may promote immunosuppression and further persistence and delayed clearance of the virus.

Figure 4

Different orchestration of cells of the immune system within the blood or lung of patients with severe SARS-CoV-2-induced disease. Monocyte-derived DCs (mDCs), non-classical monocytes, T helper 1 (Th1) cells, and myeloid-derived suppressor cells (MDSCs) are high in the peripheral blood of patients with severe disease. By contrast, CD8⁺ T cells, plasmacytoid DCs (pDCs), CD1c⁺ DCs, natural killer (NK) cells, macrophage type 2 (M2) cells, and regulatory T cells (Tregs) show low fraction within the circulation. M1 macrophages are high, whereas M2 macrophages are low within the lung of severe cases.

Figure 5

The impact of severe SARS-Cov2 induced disease on cellular immunity. In patients with a severe disease the activity of regulatory T cell (Tregs) and M2 macrophage is hampered. Whereas M1 macrophage, myeloid-derived suppressor cells (MDSCs), monocytes, neutrophils and Th1 cells show increased expansion. Other consequences of a severe infection are plasmacytoid dendritic cell (pDC) apoptosis, and CD8+ T cell and natural killer (NK) cell exhaustion.