Reduction and exhausted features of T lymphocytes under serological changes, and prognostic factors in COVID-19 progression

Mahmoodpoor, Ata; Hosseini, Maryam Sadat; Soltani‐Zangbar, Mohammad Sadegh; Sanaie, Sarvin; Aghebati‐Maleki, Leili; Saghaleini, Seyed Hadi; Ostadi, Zohreh; Hajivalili, Mahsa; Bayatmakoo, Zhinous; Haji-Fatahaliha, Mostafa; Babaloo, Zohreh; Farid, Sima Shahmohammadi; Heris, Javad Ahmadian; Roshangar, Leila; Rikhtegar, Reza; Kafil, Hossein Samadi; Yousefi, Mehdi

doi:10.1016/j.molimm.2021.06.001

Cited by 33 publications

(32 citation statements)

References 42 publications

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“…Taken together, the findings: ( i ) confirmed previous reports demonstrating broad early lymphopenia (and leukocytosis) in severely ill COVID-19 patients (11-15, 66, 67); ( ii ) demonstrated that the decrease of bulk CD3 + T cell lymphocytes numbers (affecting both CD4 + and CD8 + T cells equally) in severely ill COVID-19 patients was one major cause of this lymphopenia, but more importantly; ( iii ) that SARS-CoV-2-specific CD4 + and CD8 + T cells responding to conserved epitopes from structural, non-structural and regulatory protein antigens were even more reduced (particularly decreased relative to total reduction in T cells) in severely ill patients and in COVID-19 patients with fatal outcomes, this soon after reporting their first symptoms.…”

Section: Resultssupporting

confidence: 89%

“…We also report here that an early and broad lymphopenia positively correlated with COVID-19 disease severity and mortality, consistent with previous reports(66). Moreover, our study also confirmed previous reports of broad leukocytosis combined with T cell lymphopenia in severe COVID-19 patients and extended those findings by demonstrating the observed T cell lymphopenia was particularly apparent for SARS-CoV-2-specific T cells (11-15, 66, 67). Moreover, compared with asymptomatic COVID-19 patients, severely ill symptomatic patients and patients with fatal outcomes exhibited high frequencies of exhausted PD-1 + TIM3 + TIGIT + CTLA4 + CD4 + and PD-1 + TIM3 + TIGIT + CTLA4 + CD8 + T cells.…”

Section: Discussionsupporting

confidence: 92%

“…While about 20% of COVID-19 patients with confirmed SARS-CoV-2 infection develop severe disease(6), the mechanisms leading to this pathogenesis of COVID-19 are still incompletely understood, though it seems to involve significant immune dysregulations. Severe symptoms have been associated with: ( i ) increased levels of pro-inflammatory cytokines (driven by inflammatory monocytes and neutrophils) (8-10); ( ii ) a general lymphopenia (11-16); and ( iii ) a broad (not SARS-CoV-2-specific T cell exhaustion and/or impaired function (15-32). This was reported for immune cells both in the peripheral compartment (PBMCs) and in the lung and brain of symptomatic patients (13, 69).…”

Section: Discussionmentioning

confidence: 99%

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High Frequencies of PD-1⁺TIM3⁺TIGIT⁺CTLA4⁺ Functionally Exhausted SARS-CoV-2-Specific CD4⁺ and CD8⁺ T Cells Associated with Severe Disease in Critically ill COVID-19 Patients

Coulon

Prakash

Dhanushkodi

et al. 2022

Preprint

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SARS-CoV-2-specific memory T cells that cross-react with common cold coronaviruses (CCCs) are present in both healthy donors and COVID-19 patients. However, whether these cross-reactive T cells play a role in COVID-19 pathogenesis versus protection remain to be fully elucidated. In this study, we characterized cross-reactive SARS-CoV-2-specific CD4+ and CD8+ T cells, targeting genome-wide conserved epitopes in a cohort of 147 non-vaccinated COVID-19 patients, divided into six groups based on the degrees of disease severity. We compared the frequency, phenotype, and function of these SARS-CoV-2-specific CD4+ and CD8+ T cells between severely ill and asymptomatic COVID-19 patients and correlated this with alpha-CCCs and beta-CCCs co-infection status. Compared with asymptomatic COVID-19 patients, the severely ill COVID-19 patients and patients with fatal outcomes: (i) Presented a broad leukocytosis and a broad CD4+ and CD8+ T cell lymphopenia; (ii) Developed low frequencies of functional IFN-gamma-producing CD134+CD138+CD4+ and CD134+CD138+CD8+ T cells directed toward conserved epitopes from structural, non-structural and regulatory SARS-CoV-2 proteins; (iii) Displayed high frequencies of SARS-CoV-2-specific functionally exhausted PD-1+TIM3+TIGIT+CTLA4+CD4+ and PD-1+TIM3+TIGIT+CTLA4+CD8+ T cells; and (iv) Displayed similar frequencies of co-infections with beta-CCCs strains but significantly fewer co-infections with alpha-CCCs strains. Interestingly, the cross-reactive SARS-CoV-2 epitopes that recalled the strongest CD4+ and CD8+ T cell responses in unexposed healthy donors (HD) were the most strongly associated with better disease outcome seen in asymptomatic COVID-19 patients. Our results demonstrate that, the critically ill COVID-19 patients displayed fewer co-infection with alpha-CCCs strain, presented broad T cell lymphopenia and higher frequencies of cross reactive exhausted SARS-CoV-2-specific CD4+ and CD8+ T cells. In contrast, the asymptomatic COVID-19 patients, appeared to present more co-infections with alpha-CCCs strains, associated with higher frequencies of functional cross-reactive SARS-CoV-2-specific CD4+ and CD8+ T cells. These findings support the development of broadly protective, T-cell-based, multi-antigen universal pan-Coronavirus vaccines.

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Section: Resultssupporting

confidence: 89%

Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

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High Frequencies of PD-1⁺TIM3⁺TIGIT⁺CTLA4⁺ Functionally Exhausted SARS-CoV-2-Specific CD4⁺ and CD8⁺ T Cells Associated with Severe Disease in Critically ill COVID-19 Patients

Coulon

Prakash

Dhanushkodi

et al. 2022

Preprint

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“…The cytokine storm has been considered an important contributor to ARDS and it causes mortality for the grave SARS-CoV-2 infection cases ( Vaninov, 2020 ). The cytokine storm represents an excessive systemic inflammatory reaction where pro-inflammatory cytokines including interleukin (IL)-1β, IL-6, IL-12, IL-17, interferon (IFN)-γ, tumor necrosis factor-alpha (TNF-α), and chemokines are generated fast in large amounts in order to provide protection against SARS-CoV infection ( Channappanavar and Perlman, 2017 ; Mahmoodpoor et al, 2021 ). T-cells have the most important part in the clearance of viruses because CD8 + cytotoxic T cells (CTLs) secrete perforin, granzymes, and IFN-γ to eliminate them from the host ( Etemadi et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Serum levels of vitamin D and immune system function in patients with COVID-19 admitted to intensive care unit

et al. 2022

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Objective Vitamin D is believed to affect the functionality of the immune system for the prevention of coronavirus disease. To investigate the role of this vitamin against the Coronavirus, this study analyzed the serum levels of vitamin D, the transcription pattern of inflammatory cytokines, and the frequency of total lymphocytes, TCD4 + , TCD8 + , and NK cells in 50 COVID-19-affected subjects in comparison to 50 healthy participants. Materials and methods This study diagnosed and evaluated 100 patients. Frequency of lymphocytes was determined using flow cytometry. Cytokine expression levels were measured using Real-Time PCR. Serum levels of vitamin D and cytokines levels in cultured cell supernatant were measured by ELISA. Results Patients with COVID-19 exhibited decreased serum levels of vitamin D versus the healthy participants ( p = 0.0024). The total number of lymphocytes, TCD4 + , TCD8 + , and NK cells was significantly reduced in patients with COVID-19 ( p < 0.0001). Considerable upregulation of IL-12, IFN-γ, and TNF-α was seen in COVID-19 patients compared to the control group, whereas IFN-α was downregulated in COVID-19 patients. ELISA results also had increased levels of IL-12, TNF-α, and IFN-γ ( p = 0.0014, 0.0012, and p < 0.0001, respectively), and decreased level of IFN-α ( p = 0.0021) in patients with COVID-19 compared to the control group. Conclusion These findings suggest a probable association among vitamin D concentrations, immune system function, and risk of COVID-19 infection. As a result, it is recommended that vitamin D be considered as a candidate for handling and controlling COVID-19 because of its ability to target the cytokine storm and its antiviral effects.

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“…Mechanisms that may aggravate health conditions of patients with comorbidities infected with SARS-CoV-2 include chronical physiological changes related with chronical disease such as altered metabolism and/or immunity, which may lead to thrombosis and cytokine storm [ 28 ]. The host immune response to SARS-CoV-2 infection has an important role in the outcome of COVID-19 [ 29 ]. At the molecular level, SARS-CoV-2 infection leads to an inflammation state mainly manifested by an increase in interleukin (IL)-2, IL-7, interferon gamma (INFγ), and tumor necrosis factor alpha (TNFα) [ 30 ] and suppression of NF-kB (nuclear factor kappa B) activity, resulting in decreased expression of COX-2 (cyclooxygenase-2) [ 31 ].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the Potential Risk of Mortality from SARS-CoV-2 Infection in Hospitalized Patients According to the Charlson Comorbidity Index

et al. 2022

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Background: The pandemic of COVID-19 has represented a major threat to global public health in the last century and therefore to identify predictors of mortality among COVID-19 hospitalized patients is widely justified. The aim of this study was to evaluate the possible usefulness of Charlson Comorbidity Index (CCI) as mortality predictor in patients hospitalized because COVID-19. Methods: This study was carried out in Zacatecas, Mexico, and it included 705 hospitalized patients with suspected of SARS-CoV-2 infection. Clinical data were collected, and the CCI score was calculated online using the calculator from the Sociedad Andaluza de Medicina Intensiva y Unidades Coronarias; the result was evaluated as mortality predictor among the patients with COVID-19. Results: 377 patients were positive for SARS-COV-2. Obesity increased the risk of intubation among the study population (odds ratio (OR) = 2.59; 95 CI: 1.36–4.92; p = 0.003). The CCI values were higher in patients who died because of COVID-19 complications than those observed in patients who survived (p < 0.001). Considering a CCI cutoff >31.69, the area under the ROC curve was 0.75, with a sensitivity and a specificity of 63.6% and 87.7%, respectively. Having a CCI value >31.69 increased the odds of death by 12.5 times among the study population (95% CI: 7.3–21.4; p < 0.001). Conclusions: The CCI is a suitable tool for the prediction of mortality in patients hospitalized for COVID-19. The presence of comorbidities in hospitalized patients with COVID-19 reflected as CCI > 31.69 increased the risk of death among the study population, so it is important to take precautionary measures in patients due to their condition and their increased vulnerability to SARS-CoV-2 infection.

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Reduction and exhausted features of T lymphocytes under serological changes, and prognostic factors in COVID-19 progression

Cited by 33 publications

References 42 publications

High Frequencies of PD-1⁺TIM3⁺TIGIT⁺CTLA4⁺ Functionally Exhausted SARS-CoV-2-Specific CD4⁺ and CD8⁺ T Cells Associated with Severe Disease in Critically ill COVID-19 Patients

High Frequencies of PD-1⁺TIM3⁺TIGIT⁺CTLA4⁺ Functionally Exhausted SARS-CoV-2-Specific CD4⁺ and CD8⁺ T Cells Associated with Severe Disease in Critically ill COVID-19 Patients

Serum levels of vitamin D and immune system function in patients with COVID-19 admitted to intensive care unit

Evaluation of the Potential Risk of Mortality from SARS-CoV-2 Infection in Hospitalized Patients According to the Charlson Comorbidity Index

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Reduction and exhausted features of T lymphocytes under serological changes, and prognostic factors in COVID-19 progression

Cited by 33 publications

References 42 publications

High Frequencies of PD-1+TIM3+TIGIT+CTLA4+ Functionally Exhausted SARS-CoV-2-Specific CD4+ and CD8+ T Cells Associated with Severe Disease in Critically ill COVID-19 Patients

High Frequencies of PD-1+TIM3+TIGIT+CTLA4+ Functionally Exhausted SARS-CoV-2-Specific CD4+ and CD8+ T Cells Associated with Severe Disease in Critically ill COVID-19 Patients

Serum levels of vitamin D and immune system function in patients with COVID-19 admitted to intensive care unit

Evaluation of the Potential Risk of Mortality from SARS-CoV-2 Infection in Hospitalized Patients According to the Charlson Comorbidity Index

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High Frequencies of PD-1⁺TIM3⁺TIGIT⁺CTLA4⁺ Functionally Exhausted SARS-CoV-2-Specific CD4⁺ and CD8⁺ T Cells Associated with Severe Disease in Critically ill COVID-19 Patients

High Frequencies of PD-1⁺TIM3⁺TIGIT⁺CTLA4⁺ Functionally Exhausted SARS-CoV-2-Specific CD4⁺ and CD8⁺ T Cells Associated with Severe Disease in Critically ill COVID-19 Patients