SARS-CoV-2-reactive IFN-γ-producing CD4+ and CD8+ T cells in blood do not correlate with clinical severity in unvaccinated critically ill COVID-19 patients

Abstract

We examined the relationship between peripheral blood levels of SARS-CoV-2 S (Spike protein)1/M (Membrane protein)-reactive IFN-γ-producing CD4+ and CD8+ T cells, serum levels of biomarkers of clinical severity, and mortality in critically ill COVID-19 patients. The potential association between SARS-CoV-2-S-Receptor Binding Domain (RBD)-specific IgG levels in sera and mortality was also investigated. SARS-CoV-2 T cells and anti-RBD IgG levels were monitored in 71 non-consecutive patients (49 male and 22 female; median age, 65 years) by whole-blood flow cytometry and Enzyme-linked immunosorbent assay (ELISA), respectively (326 specimens). SARS-CoV-2 RNA loads in paired tracheal aspirates [TA] (n = 147) were available from 54 patients. Serum levels of interleukin-6, ferritin, D-Dimer, lactose dehydrogenase and C-reactive protein in paired sera were known. SARS-CoV-2 T cells (either CD4+, CD8+ or both) were detectable in 70 patients. SARS-CoV-2 IFN-γ CD4+ T-cell responses were documented more frequently than their CD8+ counterparts (62 vs. 56 patients) and were of greater magnitude overall. Detectable SARS-CoV-2 S1/M-reactive CD8+ and CD4+ T-cell responses were associated with higher SARS-CoV-2 RNA loads in TA. SARS-CoV-2 RNA load in TA decreased over time, irrespective of the dynamics of SARS-CoV-2-reactive CD8+ and CD4+ T cells. No correlation was found between SARS-CoV-2 IFN-γ T-cell counts, anti-RBD IgG concentrations and biomarker serum levels (Rho ≤ 0.3). The kinetics of both T cell subsets was comparable between those who died or survived, whereas anti-RBD IgG levels were higher across different time points in deceased patients than in survivors. Enumeration of peripheral blood levels of SARS-CoV-2-S1/M-reactive IFN-γ CD4+ and CD8+ T cells does not predict viral clearance from the lower respiratory tract or poor clinical outcomes in critically ill COVID-19 patients. In contrast, anti-RBD IgG levels were directly associated with increased mortality.

Lung T cell response in COVID-19

“…Also for CD8 + T cells, Spike, followed by M, and Nucleocapsid are the dominant antigens ( 36 – 39 ). Both SARS-CoV-2 specific CD4 + and CD8 + T cells are already identified in the first few days after symptom onset ( 40 ). Peripheral CD8 + T cells have cytotoxic function and secrete cytokines ( 41 ) with an increased frequency of HLA-DR + /CD38 + cells, especially in patients progressing to severe disease.…”

Can alpha‐linolenic acid be a modulator of “cytokine storm,” oxidative stress and immune response in SARS‐CoV‐2 infection?

“…In fact, studies have been carried out in which in hospitalized patients, an inversely proportional relationship was found between different markers of inflammation and the number of CD4 + and CD8 + T-cells (Ghizlane et al, 2021;Olea et al, 2022;Popescu et al, 2022). Several clinical studies have also shown that lymphopenia is an important prognostic factor in the case of COVID-19.…”

“…It has been observed that in severe cases, a situation of lymphopenia that aggravates the clinical picture of the patient is frequent, and that this is often strongly and significantly associated with an evident pro‐inflammatory status. In fact, studies have been carried out in which in hospitalized patients, an inversely proportional relationship was found between different markers of inflammation and the number of CD4 + and CD8 + T‐cells (Ghizlane et al., 2021; Olea et al., 2022; Popescu et al., 2022). Several clinical studies have also shown that lymphopenia is an important prognostic factor in the case of COVID‐19.…”

“…In the case of lymphocytes, a consistent number of patients with severe COVID‐19 have been found to have an associated lymphopenia (Tavakolpour et al., 2020). It was observed that this was often associated with severe inflammation status: In several studies, it was observed that CD4 + and CD8 + T cell numbers were inversely proportional to inflammation markers) (Olea et al., 2022; Popescu et al., 2022). Regarding the other types of immune response cells, it has been observed that, although moderate production of macrophages contributes to the elimination of the pathogen through various inflammatory molecules, a dysregulated response, such as that which occurs in some severe cases of COVID‐19, could further aggravate the clinical picture of the host causing, for example, the macrophage activation syndrome (MAS) (Merad & Martin, 2020).…”