In a recent study published in Scientific Reports, researchers examined the relationship between cell-mediated or T-lymphocyte-mediated immunity and the severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. .
Study: SARS-CoV-2-reactive IFN-γ-producing CD4+ and CD8+ T cells in blood do not correlate with clinical severity in unvaccinated critical COVID-19 patients. Image credit: Design_Cells/Shutterstock
background
T-lymphocyte responses facilitate SARS-CoV-2 clearance and confer protection against the severity of coronavirus disease 2019 (COVID-19). COVID-19 causes elevated T lymphocyte [CD8+ (cluster of differentiation 8+) and CD4+] counts recognizing epitopes on SARS-CoV-2 structural proteins, ie. membrane proteins (M), nucleoprotein (N) and spike (S).
Studies have reported delayed onset of SARS-CoV-2, weak interferon-gamma (IFN-γ)/interleukin-2 (IL-2) production, and dysfunctional or failed T lymphocytes more frequently among patients with severe COVID-19. In recent times, NP-targeted CD8+ T-lymphocyte counts have been significantly correlated with mild COVID-19. Data on the association between SARS-CoV-2-reactive T lymphocytes and outcomes of severity of COVID-19 are conflicting and limited.
About the study
In the present observational study, the investigators prospectively evaluated SARS-CoV-2 S1/M-reactive IFN-γ-producing T lymphocyte responses among critically ill patients with COVID-19 to explore whether SARS-CoV-2 S1/M -reactive IFN-γ T-cell counts were associated with serological biomarker indicators of poor COVID-19 outcomes and could therefore be used as surrogate markers for the prognosis of COVID-19.
The study included 71 patients with COVID-19 admitted to the intensive care unit (ICU) (22 women and 49 men, mean age 65 years), most of whom (88%) received mechanical ventilation and 28 patients they finally died. None of the patients had been vaccinated against COVID-19 on admission to the ICU. The diagnosis of COVID-19 was confirmed by RT-PCR (reverse transcription-polymerase chain reaction) analysis of nasopharyngeal swabs collected between October 2020 and February 2021 before ICU admission.
Peripheral blood samples were collected weekly during the ICU period and SARS-CoV-2 ribonucleic acid (RNA) loads were assessed in tracheal aspirates (TA) obtained from 54 patients. Counts of SARS-CoV-2 S1/M-reactive IFN-γ-producing T lymphocytes were assessed by flow cytometry (FC) analysis, and anti-RBD IgG titers were assessed by linked immunosorbent assays enzymes (ELISA). The team investigated whether there was a correlation between serological levels of ferritin, D-Dimer, IL-6, lactate dehydrogenase (LDH) and C-reactive protein (CRP) and SARS-CoV-2 reactive IFN-γ expressing CD8+ . and CD4+ T lymphocyte count.
results
SARS-CoV-2-reactive T lymphocytes (CD4+, CD8+, or both) were detected in 70 patients with severe SARS-CoV-2 infections, and 211 of 326 serum samples showed the presence of SARS-reactive T lymphocytes – CoV-2. (CD8+, CD4+ or both). The time between detectable SARS-CoV-2-reactive T cells and ICU admission and the onset of symptoms of COVID-19 was three days and 13 days, respectively.
IFN-γ-producing CD4+ T lymphocytes reactive to SARS-CoV-2 were observed more frequently (87%) than the corresponding CD8+ lymphocytes (79%). SARS-CoV-2 IFN-γ CD4+ counts fluctuated in the initial five weeks of symptom onset and increased thereafter, while CD8+ counterparts decreased over time. Of note, therapy with tocilizumab, corticosteroids, or remdesivir did not significantly affect SARS-CoV-2-reactive CD4+ or CD8+ levels.
SARS-CoV-2 CD4+ and CD8+ T-lymphocyte counts in peripheral blood showed no significant correlation with SARS-CoV-2 RNA levels in TA samples. Similarly, serum biomarker levels were not significantly correlated with peripheral blood CD8+ and CD4+ T lymphocyte counts. Median values of functional T lymphocytes were similar between groups, while anti-RBD IgG titers correlated with mortality associated with COVID-19. For SARS-CoV-2-reactive IFN-γ-producing CD8+ T lymphocytes, median values of zero cells/μL and 0.1 cells/μL were observed for patients who died of COVID-19 and survivors of COVID-19, respectively.
The corresponding medians for the CD4 + counterparts were 0.2 cells/μL and 0.3 cells/μL, respectively. In total, 326 samples obtained from 66 patients with COVID-19 showed anti-RBD IgG titers that increased up to five weeks after the onset of COVID-19 symptoms and decreased thereafter. There was no significant correlation between anti-RBD IgG titers and S1/M SARS-CoV-2 reactive functional T lymphocyte subsets. Similarly, anti-RBD IgG titers showed no significant correlation with SARS-CoV-2 RNA levels in TA samples and with serological levels of D-Dimer, IL-6, ferritin , CRP or LDH.
Conclusions
Overall, the study results showed that SARS-CoV-2 IFN-γ-producing CD4+ T lymphocytes (62 patients) were observed more frequently than their CD8+ counterparts (56 patients) and were of greater magnitude SARS-CoV-2 S1/M-reactive CD4+ and CD8+ T lymphocyte responses were associated with higher SARS-CoV-2 RNA at TA. No significant correlations were found between IFN-γ and SARS-CoV-2-expressing T-lymphocyte counts, anti-RBD IgG titers, and serum biomarker levels.
CD8+ and CD4+ counts were similar between deceased COVID-19 patients and survivors, while anti-RBD IgG titers were greater among deceased COVID-19 patients than among COVID-19 survivors. IFN-γ-expressing SARS-CoV-2-S1/M-reactive peripheral blood CD4+ and CD8+ T lymphocytes cannot be considered a predictor of SARS-CoV-2 clearance from the trachea or poor outcomes of severity of COVID-19. In contrast, anti-RBD IgG titers were positively correlated with mortality.