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).