4-1- Cell-mediated responses
When a virus is inhaled and infects the respiratory epithelial cells, DCs phagocytose the virus and present antigens to T cells. Effector T cells function through killing the infected epithelial cells, and cytotoxic CD8+ T cells produce and release pro-inflammatory cytokines which induce cell apoptosis (Rogers & Williams, 2018). Both activated CD8+ cells and anti-MERS-CoV antibodies have been reported to be crucial for the clearance of the initial infection and protection against a subsequent challenge with the virus, respectively. This finding implies that the response to MERS-CoV generally occurs through antibody-mediated immunity (J. Zhao et al., 2014). This result was confirmed when virus-specific T cells were depleted. However, this effect of cell depletion was not timely monitored at different intervals (Channappanavar, Zhao, & Perlman, 2014). Hence, the antiviral effects of the depleted cells may be important during later infection time points, leading to the persistence of the viral infection and promoting viral survival. SARS-CoV triggers and amplifies the immune response. The exacerbation of cytokine production, excessive recruitment of immune cells, and the uncontrollable epithelial damage generate a vicious circle for infection-related ARDS (C. Y. Yang et al., 2018). Moreover, during MERS-CoV infection, the virus invades the immune system and downregulates MHC-I, MHC-II, and CD80/86 in antigen-presenting cells (APCs), which subsequently inhibits the T cell response (Josset et al., 2013). These events may further impair the functions of B cells (Ying, Li, & Dimitrov, 2016). Both CD4+ and CD8+ T cells isolated from human peripheral blood, tonsils, spleens, and lymphoid organs could be infected with MERS-CoV but not with SARS-CoV. This infection pattern might be attributed to the low expression of the SARS-CoV receptor, namely, ACE2, in T cells (Ying et al., 2016).
Evidence strongly indicated that Th1 type response is a key for successful control of SARS-CoV and MERS-CoV and may be probably true for SARS-CoV-2 as well. It has been demonstrated that patients infected with SARS-CoV-2 also had high amounts of IL-1, IFN-γ, IP10, and MCP1, probably leading to activated Th1 cell responses (C. Huang et al., 2020). On the other hand, SARS-CoV-2 infection also initiates the increased secretion of Th2 cytokines (e.g., IL4 and IL10) that suppress inflammation, which differs from SARS-CoV infection (Wong et al., 2004).
Flow cytometric analyses of PBMCs from symptomatic COVID-19 patients have been indicative of a significant influx of granulocyte-macrophage colony-stimulating factor (GM-CSF)-producing and activated CD4+ T cells and CD14+HLA-DRlo monocytes (Giamarellos-Bourboulis et al., 2020; Y. Zhou et al., 2020a). In another study, a significantly increased PBMC frequency of polyclonal GM-CSF+ CD4+ T cells capable of prodigious ex vivo IL-6 and IFN-γ production in patients with severe COVID-19 has been reported (Y. Zhou et al., 2020b).
Xu et al.  showed that the peripheral blood of a patient with severe COVID-19 had a strikingly high number of CCR6+ Th17 cells (Z. Xu et al., 2020), further supporting a Th17 type cytokine storm in this disease. Elevated Th17 responses or enhanced IL-17-related pathways are also observed in MERS-CoV and SARS-CoV patients (Faure et al., 2014; Josset et al., 2013). In MERS-CoV patients, higher IL-17 level with lower amounts of IFN-γ and IFN-α have a worse outcome than the reversed phenotype (Faure et al., 2014).
Additionally, two studies have reported reduced frequencies of regulatory T cells (Treg cells) in severe COVID-19 cases (Qin et al., 2020). Since Treg cells have been shown to help resolving ARDS inflammation in mouse models (Walter, Helmin, Abdala-Valencia, Wunderink, & Singer, 2018), a loss of Treg cells might facilitate the development of COVID-19 lung immunopathology (Dong et al., 2018).
T cells seem to be more activated in severe COVID-19 and may exhibit a trend toward exhaustion based on the continuous expression of inhibitory markers such as programmed death 1 (PD-1) and T cell immunoglobulin-3 (Tim-3) as well as overall reduced activity and cytotoxicity. Conversely, recovering patients have increased count of follicular helper CD4+ T cells (TFH), decreased levels of inhibitory markers and enhanced amounts of effector molecules such as Granzyme and perforin (Thevarajan et al., 2020; Zheng et al., 2020).
Because most epitopes identified for both viruses concentrate on the viral structural proteins, it will be informative to map those epitopes identified with SARS-CoV/MERS-CoV with those of SARS-CoV-2. In SARS-CoV, lymphocyte epitopes have been extensively mapped for the structural proteins, S, N, M, and E proteins (W. J. Liu et al., 2017). Although all SARS‐CoV surface proteins, including S, M, E, and N proteins are involved in T cell responses, S protein contributes to most T-cell recognition epitopes. The overall frequency of CD8+ T cell response predominates over CD4+ T cell response (C. Huang et al., 2020; D. S. Hui et al., 2020; Panesar, 2003). In patients recovering from mild COVID-19, robust T cell responses specific for viral N, M, and S proteins have been detected by IFN-γ ELISPOT, weakly correlated with neutralizing antibody concentrations (like convalescent SARS-CoV-1 patients) (C. K. Li et al., 2008). Another report focused on S-specific CD4+ T cell responses in patients with mild to severe COVID-19 have demonstrated that such cells were present in 83% of patients with enhanced CD38, HLA-DR, and Ki-67 expression (Braun et al., 2020). Meanwhile, a low frequency of S-reactive CD4+ T cells has been detected in 34% of SARS-CoV-2 seronegative healthy control donors. However, these CD4+ T cells lacked the phenotypic markers of activation and were specific for C-terminal S protein epitopes that are highly like endemic human CoVs, suggesting that crossreactive CD4+ memory T cells in some populations (e.g., children and younger patients that experience a higher incidence of hCoV infections) may be recruited into an amplified primary SARS-CoV-2-specific response (Braun et al., 2020).
If overlapping epitopes among the three viruses can be identified, it will help design to a cross-reactive vaccine that protects against all three human coronaviruses in the future (Prompetchara et al., 2020).
In SARS-CoV survivors, the magnitude and frequency of specific CD8+ memory T cells exceeded that of CD4+ memory T cells, and virus-specific T cells persisted for at least 6–11 years, suggesting that T cells may confer long-term immunity (Ng et al., 2016; Tang, Li, Wang, & Sun, 2020). Both virus-specific CD4+ and CD8+ T cells have been detected in all patients at average frequencies of 1.4% and 1.3%, respectively. According to CD45RA and CCR7 expression status, these cells predominantly are characterized as either CD4+ T cell central memory (Tcm) or CD8+ T cell effector memory (Tem) and effector memory RA (Temra) cells. This study is notable for the use of large complementary peptide pools comprising 1,095 SARS-Cov-2 epitopes (Weiskopf et al., 2020).
In another research, in the acute phase of SARS-CoV infection, rapid reduction of lymphocytes in peripheral blood (T. Li et al., 2004), mainly T lymphocytes, was observed, and both CD4+ and CD8+ T lymphocytes were decreased. However, CD4+ T cells are more susceptible to infection. Depletion of CD4+ T cells is associated with reduced pulmonary recruitment of lymphocytes and neutralizing antibody and cytokine production, resulting in a strong immune‐mediated interstitial pneumonitis and delayed clearance of SARS-CoV from lungs (J. Chen et al., 2010). The loss of lymphocytes precedes even the abnormal changes on the chest X-ray (T. Li et al., 2003; Z. Y. Liu et al., 2003). After a one-year follow-up of SARS patients, CD3+, CD4+, and CD8+ T cells recovered rapidly during the disease recovery period, and CD8+ T lymphocytes returned to normal range within 2–3 months after the onset. The memory CD4+ T cells returned to normal a year after onset, whereas the counts of other cells including total T lymphocytes, CD3+cells, CD4+ cells, and naive CD4+ T cells were still lower than healthy controls (Xie, Fan, Li, Qiu, & Han, 2006).
Lymphopenia in SARS and COVID-19 patients is more likely to be caused by cytokines such as IFN-I, and TNF-a may inhibit T cell recirculation in blood via promoting retention in lymphoid organs and attachment to the endothelium (Kamphuis, Junt, Waibler, Forster, & Kalinke, 2006) or endogenous or exogenous glucocorticoids which ultimately leads to apoptosis of lymphocytes, rather than direct viral infection of these cells (Panesar, 2008).