Investigating the role of T-cell immunity in long COVID

A recent study published in Scientific Reports investigates the persistence of symptoms and the immune response in patients recovering from the coronavirus disease 2019 (COVID-19). 

Study: Cellular immunity reflects the persistent symptoms among COVID-19-recovered patients in Japan. Image Credit: Kateryna Kon /


Infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for the COVID-19 pandemic, can result in persistent symptoms known as ‘long COVID’ or post-acute COVID-19 syndrome (PACS).

Many studies have reported a relationship between COVID-19 and T-cell immunity, as well as a correlation between symptom duration and antigen-driven T-cell responses to the viral spike (S) protein. Thus, a T-cell assay to assess the duration of immune responses following SARS-CoV-2 infection or COVID-19 vaccination is crucial for understanding the pathophysiology of long COVID, as well as the effectiveness of current vaccines.

About the study 

Adult patients previously diagnosed with COVID-19 and recovered from the disease were included in the current study. Written informed consent was obtained from all participants.

Clinical data were collected from medical records, and blood samples were obtained from the patients. According to the severity of symptoms, patients were categorized into different groups. 

Approximately one year after blood samples were collected, a telephone survey was conducted to assess the presence and duration of persistent symptoms in recovered patients. The evaluated symptoms included fatigue, alopecia, cough, dyspnea, and dysgeusia.

The Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 was used to determine the severity of these symptoms. The survey also inquired patients about the presence of any additional subjective symptoms. 

Peripheral blood mononuclear cells (PBMCs) were isolated from blood samples using specific methods for the T-cell immune response analysis. The enzyme-linked immunosorbent spot (ELISPOT) assay was performed using SARS-CoV-2 specific antigen peptide pools, including S1, S2, and nucleocapsid (N) antigens to stimulate PBMCs and ultimately determine their reactivity. Interferon-γ (IFN-γ)-producing cell levels were monitored using an ImmunoSpot Analyzer. 

Serological testing was conducted using plasma samples obtained from the blood samples. Levels of SARS-CoV-2-specific S immunoglobulin G (S-IgG), N-IgG, various cytokines including interleukin 6 (IL-6), IL-10, IL-18, as well as chemokine ligand 9 (CXCL9), chemokine ligand 3 (CCL3), and vascular endothelial growth factor (VEGF) were measured using an immune analyzer.

Mann-Whitney U and Fisher’s exact tests were used for statistical analysis to compare differences between the experimental groups. Box plots were used to represent the data, and cluster analysis was performed using hierarchical clustering techniques.

Insufficient T-cell response increases the risk of long COVID symptoms

No significant differences were observed in the frequency, number, or duration of persistent symptoms among moderate/severe and asymptomatic/mild groups. Although not statistically significant, the asymptomatic/mild group predominantly exhibited persistent cough. These findings reveal that the severity of COVID-19 does not directly impact the occurrence or duration of persistent symptoms.

To explore the factors associated with persistent COVID-19 symptoms, the researchers examined various parameters in COVID-19-recovered patients. To this end, D-dimer levels were high in the moderate/severe group as compared to the asymptomatic/mild group. However, there were no significant differences between the two groups in other clinical parameters or time from diagnosis to collection of blood samples. 

The researchers also investigated the levels of SARS-CoV-2-specific T-cell responses, SARS-CoV-2-specific antibodies, and inflammatory cytokines in recovered patients. Significantly higher levels of SARS-CoV-2 specific antibodies and effector/memory T-cell responses were observed in these patients as compared to healthy controls. Additionally, certain inflammatory cytokines were elevated in recovered COVID-19 patients. 

A negative correlation was observed between the combined counts of SARS-CoV-2 antigens in the ELISPOT assay and the number of persistent symptoms. Patients with lower ELISPOT counts tended to experience more symptoms, thus suggesting a potential association between poor memory T-cell response and the presence of persistent symptoms in patients who have recovered from COVID-19. 

A hierarchical cluster analysis examined the relationship between the various factors measured in the study and prevalence of symptoms. No significant associations were found between antibody levels, cytokine profiles, and symptom count.

However, patients with lower ELISPOT values had a significantly higher number of persistent symptoms. Thus, insufficient T-cell immunity to SARS-CoV-2 after recovery may contribute to the presence of persistent COVID-19 symptoms. 


The current study found no significant correlation between COVID-19 severity and persistent symptoms. However, patients with inadequate T-cell immune response to SARS-CoV-2 after recovery were more likely to experience persistent symptoms.

Taken together, these findings emphasize the importance of understanding the immunological aspects of COVID-19 for better management and treatment of long-term symptoms. Furthermore, the current study highlights the potential role of T-cell immunity and the ELISPOT assay as indicators of COVID-19 progression and long-term symptoms. 

Journal reference:
Vijay Kumar Malesu

Written by

Vijay Kumar Malesu

Vijay holds a Ph.D. in Biotechnology and possesses a deep passion for microbiology. His academic journey has allowed him to delve deeper into understanding the intricate world of microorganisms. Through his research and studies, he has gained expertise in various aspects of microbiology, which includes microbial genetics, microbial physiology, and microbial ecology. Vijay has six years of scientific research experience at renowned research institutes such as the Indian Council for Agricultural Research and KIIT University. He has worked on diverse projects in microbiology, biopolymers, and drug delivery. His contributions to these areas have provided him with a comprehensive understanding of the subject matter and the ability to tackle complex research challenges.    


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