Discussion: -
We have profiled T cell populations during COVID-19 in a longitudinal
study cohort, where we followed them from inclusion up to 6-8 months
post-recovery, using spectral flow cytometry. We found wide-ranging
alterations to the T cell compartment including a rise in effectors and
effector memory T cells that lasted for a period of 6 months after
discharge from the hospital.
Lymphopenia was observed in many of the COVID-19 patients in our cohort
at inclusion (i.e., at hospitalization [11], and is a common
clinical observation [12-15] that may be attributed to the cells
relocating or dying at this stage of the disease. Indeed, a highly
inflammatory form of cell death, i.e., pyroptosis, induced in infected
and uninfected cells, appears to be a major contributing factor for the
onset of strong inflammatory responses seen globally in many individuals
with COVID-19 [8, 16-19]. Furthermore, we and others have shown that
the T cell compartment is affected to a higher degree than other immune
cells such as B or NK cells [20-23] , which implies that T cell
subsets play a paramount role in COVID-19 pathogenesis. Of note,
reductions in circulating NKT cells as illustrated by us and others
[24], have also been correlated to severe COVID-19 disease and poor
outcome [25-26].
Memory T cells, both general and antigen-specific, in the context of
SARS-CoV-2 infection have been widely studied, notwithstanding often for
shorter time-periods [27-30] with fewer long-term studies, i.e. 8-9
months [31]. Evidence from the SARS-CoV outbreak in 2005 suggests
that anti-SARS-CoV antibodies fell below detection limits within two
years [32], and SARS-CoV-specific memory T cells were detectable 11
years after the SARS outbreak [33]. Memory T cells are an important
and diverse subset of antigen experienced T cells that are sustained
long term, and when needed are converted into effector cells during
reinfection/ exposure [34, 35]. Depending on their cellular
programming and phenotype they are classified into different central and
effector memory subtypes. The effector subsets contain the CD45RA+CCR7-
TEMRA, which are essentially TEM that re-express CD45RA after antigen
stimulation [36]. Not much is known about the functionality of this
population, but CD4+ TEMRA are implicated in protective immunity
[36].
Furthermore, elevated levels of virus specific CD8+ effectors are
maintained after dengue vaccination [37]. We found an elevation of
both (CD4+ and CD8+T) effectors T cells and effectors memory T cells
that lasted throughout the study, i.e., 6-7 months which contrasted with
the CD4+ effectors that remained unaltered by COVID-19 in previous study
[38]. Previous studies have shown the CD8+ TEMRA population to be
increased at hospitalization [39,40] and sustained for 6 weeks
[39]. Currently, the exact role of CD8+ effectors in COVID-19
remains largely ambiguous, but Cohen et al. [31] found an increase
in SARS-CoV-2-specific CD8+ effectors over time. In our case, we have
explored the whole expanded CD8+ effectors and CD8+ effector memory T
cells population and cannot confirm if there was a larger fraction of
antigen-exposed, i.e., SARS-CoV-2-specific T cells, among the
population.
We found that all COVID-19 patients developed effectors T cells and
effector memory T cells, which increased over time. Our findings are in
accordance with other studies that have shown that SARS-CoV-2 infection
results in increased expansion of antigen-specific CD4+ and CD8+ T cell
subsets [41,42]. It is still unclear if the lower antigen-specific
responses seen at one month compared to 6-7 months are due to an overall
immunosuppression [43] or a natural development of the immune
response over time [44].
At present, all immunocompetent individuals develop SARS-CoV-2-specific
antibodies, which is also evident in our study. Some studies provide
clear evidence that these antibodies are detected only for a few months
after infection [45,46], whereas others support the detection for a
minimum of 6 months [47,48]. In our cohort, we found that the
increase in B cells lasted for 6-8 months post infection, even though
there was a drastic decline at some time point after 6 weeks. Our
findings are like those by Björkander et al. [42], who have reported
that the antibody responses lasted up to 8 months among young adults.
Even if the antibody levels are waning, the affinity maturation will
continue and the SARS-CoV-2-specific humoral immunity will have the
ability to provide protection against severe disease, and these
antibodies could have increased potency to neutralize the virus
[49].
With the continued burden of the current COVID-19 pandemic on the
population, there is still a need for more insight into the
SARS-CoV-2-specific immune response elicited during infection. Despite
having multiple approved and licensed vaccines, the emergence of
variants with multiple mutations [50], and the long list of
long-term symptoms following a natural SARS-CoV-2 infection [51-53],
are still cause for great concern. Further, given the likely impact of
inter-human variations in clinical parameters, more data is needed
regarding the durability and sustenance of SARS-CoV-2-specific
antibodies and T cells generated during
COVID-19 and their contribution to the quality of immune responses and
what is the lasting effect on the immune cell compartment in individuals
who that have recovered from COVID-19.
Despite the immensely challenging conditions during the pandemic, we do
believe that the cohort presented in this investigation is well
characterized and of high quality and value.
Altogether, this study highlights the alterations in the immune response
which occur during hospital treated SARS-CoV-2 infection and
convalescence. These novel longitudinal data illustrate the substantial
changes to the T cell landscape lasting for more than 6 months. Our
findings, in combination with others, are valuable in providing insight
into SARS-CoV-2 cellular and humoral immunity, and open new avenues to
be explored for improved understanding of the long-term alterations
described herein in COVID-19 immunopathogenesis.