INTRODUCTION
SARS-CoV-2, the virus responsible for COVID-19, primarily affects the respiratory system, yet its impact on T cell homeostasis is profound and far-reaching. Beyond acute infection, a subset of patients experiences persistent immunological disturbances collectively termed long COVID (LC). This study investigates how T cell immunity is altered during acute COVID-19 and long COVID by analyzing T cell receptor (TCR) formation via T-cell receptor excision circle (TREC) quantification. We collected 231 peripheral blood samples from diverse cohorts, including patients with acute COVID-19, recovered individuals, long COVID sufferers, and healthy volunteers. Using flow cytometry, we evaluated the distribution of CD4+ and CD8+ T cell subpopulations, along with TREC levels. The aim was to understand how SARS-CoV-2 reshapes T cell compartments, especially the balance of naïve, memory, and effector phenotypes. Our study reveals that COVID-19 and LC are associated with persistent immune remodeling, with implications for immune competence, recovery, and autoimmunity. These findings may help unravel the immunological underpinnings of prolonged symptoms and guide therapeutic strategies aimed at immune reconstitution.
IMMUNE CELL PROFILING IN COVID-19
Through advanced flow cytometry, we conducted a comprehensive assessment of CD4+ and CD8+ T cell subpopulations in patients across four distinct cohorts. Our profiling included subsets such as naïve, central memory (CM), effector memory (EM), and terminally differentiated effector memory (TEMRA) cells, along with functional subsets like Th1, Th2, Th17, Tfh, Tc1, Tc2, Tc17, and Tc17.1. Notably, acute COVID-19 patients exhibited a shift from naïve T cells to central memory and Th2/Tc2 polarization, alongside a decline in effector memory cells. Long COVID patients, on the other hand, showed a resurgence of naïve cytotoxic T lymphocytes (CTLs) and continued skewing toward Th2 dominance, indicating immune deviation potentially linked to chronic antigen presence or immunopathology. These alterations imply that SARS-CoV-2 not only impacts the immune response during acute infection but also causes enduring imbalances that could underlie LC symptoms.
TREC LEVELS AS A BIOMARKER OF THYMIC FUNCTION
T-cell receptor excision circles (TRECs) serve as a surrogate marker of thymic output and new T cell generation. In our study, TREC levels positively correlated with the abundance of naïve T cells, particularly in the long COVID group. This finding suggests residual thymic activity even in the post-acute phase and points toward ongoing attempts by the immune system to restore homeostasis. Interestingly, while naïve T cells were reduced in acute COVID-19, they appeared to rebound in LC, potentially due to compensatory thymic regeneration. These patterns underline the importance of TREC as a dynamic biomarker of immune recovery and a possible predictor of long-term immune competence following SARS-CoV-2 infection.
TH2 AND TH17 POLARIZATION IN LONG COVID
A defining immunological signature observed in long COVID patients was the skewing of helper T cells towards Th2 and Th17 subsets. This polarization diverges from a typical antiviral Th1-dominated response and suggests a shift toward immune profiles associated with allergy and autoimmunity. The predominance of Th2-type cytokines and depletion of Tc1/Tc2/EM subsets indicates an imbalance that may reflect chronic immune activation, inappropriate regulation, or an underlying autoimmune trigger. These findings support theories that long COVID involves elements of immune dysregulation, including loss of tolerance, persistent inflammation, and possibly molecular mimicry, which may explain prolonged and systemic symptoms in LC patients.
MEMORY T CELL DYNAMICS POST-INFECTION
Memory T cell compartments, especially central memory (CM) and effector memory (EM) cells, exhibited differential regulation across COVID-19 disease stages. Acute infection led to increased CM T cells and decreased EM1, EM3, and TEMRA populations, suggesting a redistribution or functional exhaustion of effector memory subsets. In contrast, long COVID patients showed depletion of Em2, 3, and 4 subsets, indicating impaired recall responses or altered tissue homing behavior. These changes point toward a lingering disruption in immunological memory, which may affect both antiviral defense and vaccine responsiveness in LC individuals. Understanding these shifts is crucial for developing immune-targeted interventions.
IMPLICATIONS FOR IMMUNE RECONSTITUTION AND AUTOIMMUNITY
The persistent alterations in T cell profiles observed in both acute and long COVID cases emphasize the complexity of immune reconstitution post-SARS-CoV-2 infection. The reappearance of naïve T cells and increased TREC levels in LC may reflect thymic rebound, yet the accompanying Th2/Th17 bias raises concerns over incomplete or misdirected recovery. Such patterns are reminiscent of autoimmune predisposition and may be driven by antigen persistence, dysregulated cytokine networks, or failure in immune tolerance mechanisms. These findings highlight the need for longitudinal monitoring and immunomodulatory therapies in long COVID, particularly to prevent or manage autoimmune complications that may emerge during recovery.
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#TCellImmunity, #LongCOVID, #COVID19Research, #SARSCoV2, #Immunology, #FlowCytometry, #TREC, #TCRFormation, #NaiveTCells, #EffectorMemory, #Th2Polarization, #Autoimmunity, #ImmuneDysregulation, #ThymicActivity, #CTLResponse, #ChronicInflammation, #ImmuneTolerance, #MolecularMimicry, #PostViralSyndrome, #TCellPhenotyping
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