What is the association between T lymphocyte-mediated immune responses and COVID-19 severity?

By Pooja Toshniwal PahariaAug 25 2022Reviewed by Danielle Ellis, B.Sc.

In a recent study published in Scientific Reports, researchers examined the relationship between cell-mediated or T lymphocyte-mediated immunity and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection severity.

Background

T lymphocyte responses facilitate SARS-CoV-2 clearance and confer protection against coronavirus disease 2019 (COVID-19) severity. COVID-19 results in elevated T lymphocyte [CD8+ (cluster of differentiation 8+) and CD4+] counts that recognize epitopes in SARS-CoV-2 structural proteins viz. the membrane (M), nucleoprotein (N), and spike (S) proteins.

Studies have reported delayed SARS-CoV-2 appearance, weak interferon-gamma (IFN-γ)/interleukin-2 (IL-2)-production, and dysfunctional or misfired T lymphocytes with greater frequency among severe COVID-19 patients. 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 COVID-19 severity outcomes are contradictory and limited.

About the study

In the present observational study, researchers prospectively assessed SARS-CoV-2 S1/M-reactive IFN-γ-producing T lymphocyte responses among critically ill COVID-19 patients to explore if 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 COVID-19 prognosis.

The study comprised 71 intensive care unit (ICU)-admitted COVID-19 patients (22 women and 49 men, median age of 65 years), most of whom (88%) received mechanical ventilation, and 28 patients eventually died. None of the patients had received COVID-19 vaccinations at ICU admission. COVID-19 diagnosis was confirmed by RT-PCR (reverse transcription-polymerase chain reaction) analysis of nasopharyngeal swabs collected between October 2020 and February 2021 before ICU admissions.

Peripheral blood samples were collected weekly during the ICU period, and SARS-CoV-2 ribonucleic acid (RNA) loads were evaluated in tracheal aspirates (TA) obtained from 54 patients. SARS-CoV-2 S1/M-reactive IFN-γ-producing T-lymphocyte counts were evaluated by flow cytometry (FC) analysis, and anti-RBD IgG titers were assessed by enzyme-linked immunosorbent assays (ELISA). The team investigated if 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 counts.

Results

SARS-CoV-2-reactive T lymphocytes (CD4+, CD8+ or both) were detected in 70 patients with severe SARS-CoV-2 infections, and 211 out of 326 serum samples showed the presence of SARS-CoV-2-reactive T lymphocytes (CD8+, CD4+, or both). The duration elapsed between detectable SARS-CoV-2-reactive T lymphocytes and ICU admissions and onset of COVID-19 symptoms were three days and 13 days, respectively.

SARS-CoV-2-reactive IFN-γ-producing CD4+ T lymphocytes were observed with greater frequency (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, whereas the CD8+ counterparts waned with time. Of note, tocilizumab, corticosteroid, or remdesivir therapy did not significantly impact 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. Likewise, serum biomarker levels did not correlate significantly with peripheral blood CD8+, and CD4+ T lymphocyte counts. The median values for functional T-lymphocytes were similar across groups, whereas anti-RBD IgG titers correlated with COVID-19-associated mortality. For SARS-CoV-2-reactive IFN-γ-producing CD8+ T lymphocytes, median values of zero cell/μL and 0.1 cell/μL were observed for dead COVID-19 patients and COVID-19 survivors, respectively.

The corresponding medians for the CD4+ counterparts were 0.2 cell/μL and 0.3 cell/μL, respectively. In total, 326 samples obtained from 66 COVID-19 patients showed anti-RBD IgG titers that increased up to five weeks after the onset of COVID-19 symptoms and reduced thereafter. There was no significant correlation between the anti-RBD IgG titers and the SARS-CoV-2 S1/M-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 D-Dimer, IL-6, ferritin, CRP, or LDH levels.

Conclusions

Overall, the study findings showed that SARS-CoV-2 IFN-γ-producing CD4+ T-lymphocytes (62 patients) were more frequently observed than their CD8+ counterparts (56 patients) and were of higher magnitude. SARS-CoV-2 S1/M-reactive CD4+ and CD8+ T-lymphocyte responses were associated with higher SARS-CoV-2 RNA in TA. No significant correlations were found between SARS-CoV-2-reactive and IFN-γ-expressing T lymphocyte counts, anti-RBD IgG titers, and serum biomarker levels.

CD8+ and CD4+ counts were similar among deceased COVID-19 patients and survivors, whereas anti-RBD IgG titers were greater among deceased COVID-19 patients than COVID-19 survivors. Peripheral blood SARS-CoV-2-S1/M-reactive IFN-γ-expressing CD4+ and CD8+ T lymphocytes could not be considered a predictor of SARS-CoV-2 clearance from the trachea or poor COVID-19 severity outcomes. Contrastingly, anti-RBD IgG titers positively correlated with mortality.