COVID-19 News: Study Reveals That SARS-CoV-2 Causes Impaired Homeostasis Of T Follicular Helper Cells In The Elderly

COVID-19 News: As the world grappled with the evolving landscape of the COVID-19 pandemic, China witnessed a significant shift in its approach to managing the crisis in December 2022. The discontinuation of the dynamic zero policy resulted in a nationwide surge of COVID-19 cases and hospitalizations. Particularly vulnerable to the severe consequences of the virus, elderly individuals bore the brunt of the impact. To shed light on the immune response in this demographic, researchers from Tianjin Medical University and Tianjin Medical University General Hospital in China conducted a comprehensive study. Their findings, covered in this COVID-19 News report, reveal crucial insights into the immune profile of elderly patients with acute COVID-19 and the potential of specific cell populations as biomarkers for risk stratification.


Activation signatures of T cells in geriatric. T cell activation assays of PBMCs were performed after peptide pool stimulation. Percentages of (A) CD38+HLA-DR+CD4+ and (B) CD69+CD137+CD4+ in healthy donors (HDs), MPs, SPs, DPs and CDs. Spearman correlation analyses between CD69+CD137+CD4+ percentage and (C) age (D) SpO2% and (E) PaO2/FiO2 (mm Hg). Percentages of (F) CD38+CD4+ and (G) HLA-DR+CD4+ in MPs, SPs, DPs. Spearman correlation analyses between CD38+CD4+ (green) or HLA-DR+CD4+ (purple) percentages with (H) SpO2% (I) PaO2 / FiO2 (mm Hg) (J) APACHE Score and (K) WHO Ordinal Scale score. Convalescent donors were not included in Spearman correlation analyses. All data of dot plots are displayed as mean ± SEM and analyzed by One-way-ANOVA with Tukey correction or Kruskal-Wallis test according to data distribution. *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001, ****p ≤ 0.0001.

The Context of Aging and COVID-19
The backdrop against which this study unfolds is the United Nations Decade of Healthy Aging (2021–2030), coinciding with the COVID-19 pandemic. China, undergoing rapid demographic changes, faced a significant challenge in managing the health outcomes of its aging population. The study period, from December 2022 to February 2023, saw a drastic shift in COVID-19 maintenance policies, leading to the first nationwide wave of COVID-19-related cases and hospitalizations. The impact on the elderly was profound, with individuals aged ≥ 65 years accounting for a staggering 91% of the COVID-19-related deaths during this period.
 
Immunosenescence, characterized by age-related immune function decline and dysregulation, heightened the vulnerability of the elderly to severe COVID-19 and poor outcomes. Lymphopenia, a reduction in the number of lymphocytes, emerged as a key hematological biomarker associated with severe COVID-19. T cell clonal expansion, essential for effective anti-viral responses and immune memory, showed age-dependent decline. Understanding the dynamics of T cell subsets susceptible to immunosenescence and their relationship with COVID-19 severity became a critical area for exploration.
 
The Study's Objectives and Design
The primary objectives of the study were to probe the immu ne profile of elderly patients with acute COVID-19 and explore the feasibility of using specific cell populations as biomarkers for risk stratification. The researchers recruited 57 elderly patients with acute COVID-19 and 27 convalescent donors to assess SARS-CoV-2-specific adaptive immunity. This included evaluating binding antibodies, neutralizing antibodies, and T-cell responses across the spectrum of COVID-19 severity.
 
Results - CD4+ T Cell Homeostasis and Impaired Immune Responses
The findings revealed that elderly patients with acute COVID-19 experienced severity-dependent CD4+-biased lymphopenia following SARS-CoV-2 infection. This age-dependent decline in CD4+ T cell homeostasis correlated with the severity of acute respiratory distress syndrome (ARDS). Notably, the impairment of T follicular helper (Tfh) cell subsets, including Tfh-em, Tfh-cm, Tfh1, Tfh2, Tfh17, and T follicular regulatory cells (TFR), was observed. These Tfh subsets play a crucial role in supporting high affinity and long-term antibody responses.
 
The study highlighted a correlation between the degree of Tfh deficiency and the severity of ARDS, suggesting the potential use of these Tfh subsets as biomarkers for risk stratification in elderly patients with COVID-19. Vaccination emerged as a positive contributor, ameliorating Tfh and TFR deficiency and promoting neutralizing antibody (NAbs) production.
 
Background and Immunological Insights
The study placed its findings within the broader context of the impact of aging on immune function and the need for a coordinated assessment of adaptive immunity across the COVID-19 severity spectrum. While immunosenescence and lymphopenia were recognized as significant factors, the study delved into the intricate details of T cell subsets and their susceptibility to aging and COVID-19 severity.
 
The immune profiling extended beyond the acute phase of infection, considering convalescent individuals and vaccination as factors influencing immune responses. The World Health Organization's emphasis on inadequate vaccine coverage among people aged ≥ 60 years highlighted a critical gap in understanding the impact of vaccination, combined with COVID-19 policy changes, on older adults in China.
 
Implications and Correlations: Tfh Subsets, TFR, and Antibody Responses
The severity-dependent impairment of Tfh subsets and TFR during acute COVID-19 in the elderly emerged as a significant finding. The study classified Tfh subsets into Tfh1, Tfh2, and Tfh17, noting their varying contributions to antibody production. TFR, thought to regulate germinal center (GC) and antibody production, exhibited a decline in proportion as COVID-19 severity increased.
 
Correlation analyses revealed associations between Tfh-cm, Tfh-em, Tfh2, TFR, and clinical indicators such as age, respiratory parameters, and disease severity. The study suggested that Tfh-cm, representing a relatively quiescent state of Tfh, could serve as a reliable biomarker for evaluating the severity status of patients with COVID-19. Importantly, the decline in TFR was implicated in insufficient antibody production, indicating a potential interplay between TFR deficiency and uncontrolled cytotoxic Tfh elevation.
 
Vaccination as a Mitigating Factor
The study investigated the impact of vaccination on immune responses in elderly patients. Notably, vaccination contributed to the alleviation of CD4+ T cell disturbance, with a specific focus on the recovery of Tfh subsets and TFR. The increase in Tfh-em, Tfh-cm, Tfh2, and TFR percentages was synchronous with enhanced neutralizing antibody (NAbs) production. The study underscored the role of vaccination in attenuating T cell imbalance, restoring Tfh homeostasis, and promoting robust antibody responses.
 
Conclusion: Implications for Prognosis and Public Health
The study's findings have significant implications for understanding the immunological dynamics in elderly patients with COVID-19. The severity-dependent decline in Tfh subsets, TFR, and the potential role of vaccination in mitigating these deficiencies suggest avenues for risk stratification and therapeutic interventions. Tfh-cm emerged as a promising biomarker for assessing the severity status of patients, providing a valuable tool for prognosis.
 
As China and the world navigate the complexities of the COVID-19 pandemic, the study emphasizes the importance of considering the unique immunological challenges faced by the elderly population. Vaccination, recognized as a primary defense, not only addresses acute immune responses but also plays a crucial role in restoring immunophenotypic balance in older adults. Further research is warranted to explore the nuanced relationship between vaccination history and patient outcomes, paving the way for more targeted and effective public health interventions.
 
The study findings were published on a preprint server and are currently being peer reviewed.
https://www.researchsquare.com/article/rs-3629075/v1
 
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