Activation of cytotoxic T cell population and inversion of CD4:CD8 ratio as manifestations of cellular immune response in SARS-COV-2 infection

Khan, Fahad; Akker, Tayler van den; Hussein, Shafinaz; Marcellino, Bridget; Khattar, Pallavi; Glicksberg, Benjamin S.; Nadkarni, Girish N.; Firpo-Betancourt, Adolfo; Jamal, Siraj M. El

doi:10.1007/s12308-020-00405-9

Cited by 9 publications

(7 citation statements)

References 11 publications

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“…We also found no difference in the frequency of γδ T cells, iNKT cells, or MAIT cells or in B cells, monocytes, or NK cells ( Figure 1G and Supplemental Figure 5, A and B ). However, the frequency of activated CD8 + T cells was significantly higher among hospitalized subjects, which is consistent with prior reports ( Figure 1F ) ( 19 , 36 , 37 ). The frequency of naive CD8 + T cells was also lower among hospitalized subjects, suggesting increased differentiation to an effector phenotype in severe COVID-19; however, no difference in the frequency of naive CD4 + T cells was observed between groups ( Figure 1H ).…”

Section: Resultssupporting

confidence: 93%

Comorbid illnesses are associated with altered adaptive immune responses to SARS-CoV-2

Yu¹,

Fischinger²,

Smith³

et al. 2021

JCI Insight

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Comorbid medical illnesses, such as obesity and diabetes, are associated with more severe COVID-19, hospitalization, and death. However, the role of the immune system in mediating these clinical outcomes has not been determined. We used multi-parameter flow cytometry and systems serology to comprehensively profile the functions of T cells and antibodies targeting spike, nucleocapsid, and envelope proteins in a convalescent cohort of COVID-19 subjects who were either hospitalized (n=20) or not hospitalized (n=40). To avoid confounding, subjects were matched by age, sex, ethnicity, and date of symptom onset. Surprisingly, we found that the magnitude and functional breadth of virusspecific CD4 T cell and antibody responses were consistently higher among hospitalized subjects, particularly those with medical comorbidities. However, an integrated analysis identified more coordination between polyfunctional CD4 T-cells and antibodies targeting the S1 domain of spike among subjects that were not hospitalized. These data reveal a functionally diverse and coordinated response between T cells and antibodies targeting SARS-CoV-2, which is reduced in the presence of comorbid illnesses that are known risk factors for severe COVID-19.

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Section: Resultssupporting

confidence: 93%

Comorbid illnesses are associated with altered adaptive immune responses to SARS-CoV-2

Yu¹,

Fischinger²,

Smith³

et al. 2021

JCI Insight

View full text Add to dashboard Cite

show abstract

“…We also found no difference in the frequency of γδ T cells, invariant NKT cells, or mucosal associated invariant T cells as well as B cells, monocytes, or NK cells (Figure 1G and Supplementary Figure 4). However, the frequency of activated CD8+ T cells was significantly higher among hospitalized subjects, which is consistent with prior reports (Figure 1I) (21, 38, 39). The frequency of naive CD8+ T cells was also lower among hospitalized subjects, suggesting differentiation to an effector phenotype after SARS-CoV-2 infection (Figure 1J).…”

Section: Resultssupporting

confidence: 93%

T cell and antibody functional correlates of severe COVID-19

Fischinger

Smith

et al. 2020

Preprint

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Comorbid medical illnesses, such as obesity and diabetes, are associated with more severe COVID-19, hospitalization, and death. However, the role of the immune system in mediating these clinical outcomes has not been determined. We used multi-parameter flow cytometry and systems serology to comprehensively profile the functions of T cells and antibodies targeting spike, nucleocapsid, and envelope proteins in a convalescent cohort of COVID-19 subjects who were either hospitalized (n=20) or not hospitalized (n=40). To avoid confounding, subjects were matched by age, sex, ethnicity, and date of symptom onset. Surprisingly, we found that the magnitude and functional breadth of virus-specific CD4 T cell and antibody responses were consistently higher among hospitalized subjects, particularly those with medical comorbidities. However, an integrated analysis identified more coordination between polyfunctional CD4 T-cells and antibodies targeting the S1 domain of spike among subjects that were not hospitalized. These data reveal a functionally diverse and coordinated response between T cells and antibodies targeting SARS-CoV-2 which is reduced in the presence of comorbid illnesses that are known risk factors for severe COVID-19. Our data suggest that isolated measurements of the magnitudes of spike-specific immune responses are likely insufficient to anticipate vaccine efficacy in high-risk populations.

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“…In 46% of convalescents, this ratio was below 1.5. Such disturbances were already observed in COVID-19 patients (64). Interestingly, our research showed a strong association between CD4 + /CD8 + ratio and neutrophil count, suggesting that cells of granulocyte origin may have an impact on this parameter, most likely affecting frequency of CD8 + T cells.…”

Section: Discussionsupporting

confidence: 74%

“…To the best of our knowledge, this is the first study documenting such an observation in convalescents after mild or asymptomatic infection. In the case of convalescents, we did not observe, typical for acute COVID–19 lymphopenia ( 63 , 64 ), which is associated with severe disease ( 6 , 65 ) and usually is reversed when patients recover ( 6 , 66 ). In some patients, lymphopenia has been reported to affect CD4 + and CD8 + T cells, and other lymphocytes ( 12 , 45 , 66 ), whereas many data suggest that SARS–CoV–2 infection has a preferential impact on CD8 + T cells ( 63 , 67 ).…”

Section: Discussioncontrasting

confidence: 65%

Mild and Asymptomatic COVID-19 Convalescents Present Long-Term Endotype of Immunosuppression Associated With Neutrophil Subsets Possessing Regulatory Functions

et al. 2021

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The SARS-CoV-2 infection [coronavirus disease 2019 (COVID-19)] is associated with severe lymphopenia and impaired immune response, including expansion of myeloid cells with regulatory functions, e.g., so-called low-density neutrophils, containing granulocytic myeloid-derived suppressor cells (LDNs/PMN-MDSCs). These cells have been described in both infections and cancer and are known for their immunosuppressive activity. In the case of COVID-19, long-term complications have been frequently observed (long-COVID). In this context, we aimed to investigate the immune response of COVID-19 convalescents after a mild or asymptomatic course of disease. We enrolled 13 convalescents who underwent a mild or asymptomatic infection with SARS-CoV-2, confirmed by a positive result of the PCR test, and 13 healthy donors without SARS-CoV-2 infection in the past. Whole blood was used for T-cell subpopulation and LDNs/PMN-MDSCs analysis. LDNs/PMN-MDSCs and normal density neutrophils (NDNs) were sorted out by FACS and used for T-cell proliferation assay with autologous T cells activated with anti-CD3 mAb. Serum samples were used for the detection of anti-SARS-CoV-2 neutralizing IgG and GM-CSF concentration. Our results showed that in convalescents, even 3 months after infection, an elevated level of LDNs/PMN-MDSCs is still maintained in the blood, which correlates negatively with the level of CD8+ and double-negative T cells. Moreover, LDNs/PMN-MDSCs and NDNs showed a tendency for affecting the production of anti-SARS-CoV-2 S1 neutralizing antibodies. Surprisingly, our data showed that in addition to LDNs/PMN-MDSCs, NDNs from convalescents also inhibit proliferation of autologous T cells. Additionally, in the convalescent sera, we detected significantly higher concentrations of GM-CSF, indicating the role of emergency granulopoiesis. We conclude that in mild or asymptomatic COVID-19 convalescents, the neutrophil dysfunction, including propagation of PD-L1-positive LDNs/PMN-MDSCs and NDNs, is responsible for long-term endotype of immunosuppression.

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Activation of cytotoxic T cell population and inversion of CD4:CD8 ratio as manifestations of cellular immune response in SARS-COV-2 infection

Cited by 9 publications

References 11 publications

Comorbid illnesses are associated with altered adaptive immune responses to SARS-CoV-2

Comorbid illnesses are associated with altered adaptive immune responses to SARS-CoV-2

T cell and antibody functional correlates of severe COVID-19

Mild and Asymptomatic COVID-19 Convalescents Present Long-Term Endotype of Immunosuppression Associated With Neutrophil Subsets Possessing Regulatory Functions

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