Table 1.

The role of immune cells in inflammation, homeostasis, and SARS-CoV-2 pathophysiology.

Innate immune cells
Immune cells	Immune cell function in inflammation and homeostasis	Emerging clinical relevance in SARS-CoV-2 infection
Neutrophils	Neutrophils are first responders at the site of infection and contribute to acute lung injury (27). Apart from its role in inflammation, apoptosis of neutrophils serves as a signal for withdrawal of tissue damage (28).	Neutrophil responsive chemokine signature, secretion of NET (Neutrophil extra-cellular traps), and increased infiltration of neutrophils were found to be associated with severe cases of COVID-19 (29–32).
Mast cells	Mast cells with poor regulation of pre-formed inflammatory granules can lead to severe pathology of the lungs (33). In addition to inflammatory function, mast cells can contribute to homeostatic functions through the secretion of anti-inflammatory cytokines and wound healing processes (34).	Dysfunctional mast cells and release of histamines leads to hyperinflammation hyperinflammatory cytokine storm in COVID 19 patients with severe disease (35, 36).
Basophils	Basophils are similar in function to mast cells and release pre-formed mediators upon IgE-induced activation (37, 38). Basophils in the lungs have been shown to maintain lung homeostasis by regulating the maturation and function of alveolar macrophages (39).	Basophils are reduced in the acute phase but increase in the recovery phase. Basophils were found to enhance B cell response and production of strong IgG antibody titers (40).
Eosinophils	Eosinophils can exacerbate tissue damage by contributing inflammatory cytokines and lipid mediators (38). In normal conditions, eosinophils play several roles including glucose homeostasis, immunomodulation, and other biological functions (41).	IFN-γ triggered expansion of CD62L+ Eosinophils contributes to ARDS. Eosinophil levels were found to increase in the recovery phase of COVID-19 patients (40).
Dendritic cells	Airborne pathogens and debris are removed by lung-resident dendritic cells. These cells cross-present antigens to naïve T cells after migrating to lymph nodes to activate immune response (42).	Impaired functionality of dendritic cells was found in SARS-CoV-2 infected patients (43).
Monocytes	Monocytes along with granulocytes have been shown to emigrate to naïve tissues for maintenance of normal tissue functions (44). In diseased conditions, pulmonary monocytes can initiate and activate CD8+ T cells in the lungs during infection (45).	SARS-CoV-2 induces mixed M1/M2 phenotype in circulating monocytes (46).
Macrophages	Macrophages contribute the majority of cellular immune content in homeostatic lungs and are composed of three subtypes: bronchial macrophages, interstitial macrophages, and alveolar macrophages (42).	Patients with higher viral load demonstrated T cell exhaustion and correlated with CCL15 expressing M1-like macrophages (47).
Adaptive immune cells
B cells	Among all immunoglobulins, IgA is the most prevalent in the lungs and is secreted by B cells and plasma cells (48).	A reduced number of ‘Naturally effector’ B cells were found in COVID-19 patients (49).
Plasmablasts	Plasmablasts mature into plasma cells that secrete IgA, IgM, IgD, IgG, and IgE, essential for contributions to the health and disease of lungs (48).	PBs showed metabolic shift to higher amino-acid metabolic pathways in severe patients which is reduced in convalescent-phase (50).
CD4 T cells	Naïve T cells can differentiate into effector or memory T cells upon exposure to antigen through antigen-presenting cells (APCs) (51).	SARS-CoV-2 infected patients showed TH1 cytokine profile (52).
CD8 T cells	CD8+ T cells produce IFN-γ, TNF-α, and IL-2, which leads to the killing of infected cells using cytotoxic granules (granzyme and perforin) (51).	Decrease in CD8+ T cells in severe cases (32).
T memory cells	T resident memory cells are present in the lungs for rapid control of respiratory viral infections (53).	Long-lasting T cell immunity was found to be present in COVID-19 recovered patients (54).
B memory cells	Resident memory B cells play a significant role in the adaptive immunity of lungs (55).	B memory cell response persists after the recovery phase (56).
T-regulatory cells	T regulatory cells in the lungs promote tolerance to inhaled antigens and prevent excessive inflammation (57).	Reduction of T-reg cells was observed in severe to moderate COVID-19 patients (58–60).
Other immune cells
Monocytic myeloid-derived suppressive cells (M-MDSCs)	MDSCs are present in pathological conditions such as infection or cancer (61).	Higher frequency of M-MDSCs in acute patients (43).
Polymorphonuclear (PMN)-MDSC		Expansion of PMN-MDSCs correlated with ICU patients and inflammatory cytokines: IL-1β, IL-6, IL-8, and TNF (62).
NK cells	NK cells provide immunity against viral infections through antibody-dependent cellular cytotoxicity and cytotoxic lysis (63). In steady conditions, lung NK cells are predominantly in the hypofunctional state to prevent unwanted, excessive inflammation (63).	Lowered NK cells and effector functionality (64).
NK memory cells	Memory-like NK cells with robust recall properties can play a vital role during viral infection (65).	A significantly higher number of memory NK cells in deceased patients (66).
Innate lymphoid cells	During infection, Innate lymphoid cells play a critical role in the repair of mucosal surfaces (67). After infection, these cells promote pulmonary homeostasis through mechanisms such as wound healing and upregulation of amphiregulin (68).	Severe patients had a lower frequency of ILCs (69).
Gamma delta T cells (γδT cells)	γδT cells have both innate and adaptive features for protection against invading pathogens (70).	Depleted levels of γδT cells were found in severe patients (49).
Mucosa-associated invariant T cells (MAIT cells)	MAIT cells are activated by conserved pathogenic ligands and play a protective role (71).	MAIT cells are actively recruited to inflamed airways of COIVD-19 patients. There was a significant reduction in MAIT cells in severe COVID-19 patients (69, 72).
TH17 cells	TH17 inhibits Th1 type immune response and can contribute to immunopathology during viral infections (73). In a steady state, IL-17A plays an important role in the repair and maintenance of epithelial cell homeostasis (74).	TH17 activation has been associated with severe COVID-19 symptoms (75).