Critical COVID-19 infection characterized by a shift from naïve T cell phenotypes to an expansion of cytotoxic CD4+ T lymphocyte subsets

In a recent study posted to the medRxiv* preprint server, researchers immunophenotyped T lymphocyte responses among unvaccinated individuals, representative of the entire spectrum of the clinical presentation of coronavirus disease 2019 (COVID-19).

Study: A unique cytotoxic CD4+ T cells signature defines critical COVID-19. Image Credit: Design_Cells/Shutterstock.com
Study: A unique cytotoxic CD4+ T cells signature defines critical COVID-19. Image Credit: Design_Cells/Shutterstock.com

*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Background

COVID-19 had varied clinical presentations, ranging between asymptomatic infections and fatal infections. Neutralizing antibody (nAb) titers are associated with immunity against severe and symptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections.

However, the role of T-lymphocyte responses and cell-mediated immunity in preventing COVID-19 progression is not clear, the assessment of which could inform next-generation SARS-CoV-2 vaccine development.

About the study

In the present study, researchers reported on the immunological cytotoxic cluster of differentiation 4+ (CD4+) T lymphocyte signature of critical COVID-19.

Peripheral blood mononuclear cell (PBMC) samples were obtained from polymerase chain reaction (PCR)-confirmed COVID-19 patients and subjected to spectral cytometry analysis. Manual and computational analyses were performed to detect T lymphocyte populations related to distinctive disease states via non-biased clustering, discriminant analysis, and principal component analysis (PCA).

The team explored T lymphocyte populations that might be involved in COVID-19 progression of severity using partial least squares discriminant analysis (PLS-DA). Memory and naïve lymphocyte subset distribution was explored among CD4+ non-follicular helper T lymphocyte and CD8+ T lymphocyte compartments.

Further, the proportions of cytotoxic CD4+ T lymphocytes and CD8+ T lymphocytes were correlated to determine whether CD4+ cytotoxicity might compensate for CD8+ T lymphocyte exhaustion. A phenotypic analysis of T lymphocyte responses was performed for individuals with asymptomatic to critical COVID-19.

Results

Critical COVID-19 was characterized by the elevated cytotoxic and activated type of CD4+ T lymphocyte of T follicular helper (TFH) type or the effector memory re-expressing CD45RA (TEMRA) phenotype. The CD4+ cytotoxic T lymphocytes (CTLs) were rarely present among severe COVID-19 patients. Contrastingly, mild or asymptomatic COVID-19 was related to elevated percentages of non-activated or naïve type of T lymphocytes and lowered activation marker expression.

The proportions of CD8+ CD45RO- and C-C chemokine receptor type 7+ (CCR7+) cells and CD4+, CD45RO-, and CCR7+ cells were found to be significantly higher among severe COVID-19 patients than those with critical infection, denoting naïve or inactivated (TN) CD8+ T lymphocytes and CD4+ T lymphocytes, respectively. The findings indicated that critical COVID-19 was characterized by a shift from naïve T lymphocyte phenotypes to cytotoxic CD4+ T lymphocyte subset expansion.

The proportion of circulating programmed cell death protein-1 (PD-1+) CCR7- TFH lymphocytes (cTFH) was greater among critical COVID-19 patients. Cytotoxic CD4+ T lymphocytes comprised 3.70% of lymphocytes among critical COVID-19 patients and 0.4 to 1.3% among all other COVID-19 patients. In the compartment of CD4+ non-follicular helper T lymphocytes, greater proportions of CD4+ TEMRA lymphocytes expressing granzyme B (GZMB+) and perforin (PFN+) were observed among critical COVID-19 patients.

Critical COVID-19 patients showed elevated percentages of CD8+ TEMRA lymphocytes and lowered proportions of CD4+ TN lymphocytes compared to patients with mild or severe COVID-19. In addition, critical COVID-19 patients showed elevated human leukocyte antigen-DR isotype (HLA-DR) expression on CD4+ TEMRA cells compared to individuals with mild or asymptomatic COVID-19, with considerably greater proportions of CD8+ TEMRA lymphocytes expressing PD-1, with COVID-19 progression.

The findings indicated that cytotoxic CD4+ TEMRA and cTFH lymphocyte expansion was characteristic of critical COVID-19. The increased HLA expression among respiratory epithelial cells provides a probable mechanistic basis for the contribution of CD4+ CTLs in host tissue injury associated with acute respiratory distress syndrome (ARDS) among individuals with SARS-CoV-2 infections.

There was no change in percentages of CD8+ GZMB+ PFN+ subsets across COVID-19 severities, indicating that CD8+ CTL exhaustion, if present, was not a characteristic feature of COVID-19 progression. The T lymphocyte compartment was distinctly altered among critical COVID-19 patients, with expanded effector memory cell subsets and elevated expression of cytotoxic and activation functional type of markers on CD4+ T lymphocytes. The findings indicate a probably pathogenic contribution of the cytotoxic type of CD4+ CTLs in COVID-19 progression.

Conclusion

The study findings showed that highly activated and cytotoxic clusters of differentiation 4+ T lymphocyte responses might contribute to cell-mediated host tissue injury and COVID-19 progression. The probability for induction of the detrimental T lymphocyte responses must be considered while developing and executing effective SARS-CoV-2 containment strategies.

Since data on cytotoxic cTFH in SARS-CoV-2 infections are limited, the implications of cytotoxicity in cTFH lymphocytes need further analysis evaluating the probable detrimental effects that cTFH lymphocytes might have on anti-SARS-CoV-2 humoral immunity responses.

*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Pooja Toshniwal Paharia

Written by

Pooja Toshniwal Paharia

Pooja Toshniwal Paharia is an oral and maxillofacial physician and radiologist based in Pune, India. Her academic background is in Oral Medicine and Radiology. She has extensive experience in research and evidence-based clinical-radiological diagnosis and management of oral lesions and conditions and associated maxillofacial disorders.

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