Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the COVID-19 pandemic, has evolved into numerous variants exhibiting increased resistance to neutralizing antibodies (nAbs) induced by natural infection or vaccination [1,2]. The Omicron variant (B.1.1.529) is notable for its high mutation count and altered infection route. Further divergence into subvariants (BA.2, BA.3, BA.4, BA.5, BQ.1, BQ.1.1) raises concerns about vaccine efficacy, and reinfections even in vaccinated individuals highlight immunological escape [3,4,5]. Adaptive immune responses, particularly cell-mediated immunity, are crucial for controlling SARS-CoV-2 infection [6]. The rapid evolution of SARS-CoV-2 and its variants underscores the importance of cellular immunity [7]. Strong T-cell responses correlate with less severe infections, but hyperactivation can worsen the disease. Importantly, T cells possess long-term memory, enabling responses to variants like Delta and Omicron by targeting conserved epitopes [8,9]. In viral infections, CD4+ and CD8+ T cells perform distinct immunological functions, supporting innate immunity in controlling viral replication and antibody-mediated infection control [1,10]. Previous findings on SARS-CoV-1 and MERS suggest that T cells may be key facilitators in viral infection control [11,12]. An integrated cell-mediated response is crucial alongside innate immunity (Figure 1) [13,14]. Early cytotoxic CD8+ T cell development correlates with efficient viral clearance, mild disease [15,16], and aligns with adaptive immune response kinetics [15,17,18]. A portion of this response might be attributed to bystander CD8+ T cells, contributing to protection by secreting interferon-gamma but also causing host damage through cytotoxic activity [16,19,20]. Up to 20% of COVID-19 patients exhibit inadequate adaptive immunity, suggesting potential benefits from early antibody treatment despite strong cellular responses in most patients [7]. In young individuals, SARS-CoV-2 might cross-react with T cells from seasonal coronavirus infections, leading to infection resistance. This cross-reactivity, due to similarities between SARS-CoV-2 and endemic coronaviruses (HCoVs), might explain less severe COVID-19 in young populations [21,22,23]. Non-SARS-CoV-2-specific T cells might reduce infection severity. Conversely, SARS-CoV-2 infection in the elderly could be linked to reduced cross-reactive T cells. However, the lack of CD4+ T cell cross-reactivity between endemic beta-coronaviruses and SARS-CoV-2 suggests alternative mechanisms [24]. Significant changes in the S-proteins of variants like Omicron and Delta affect CD4+ T cell recognition, impairing cross-reactivity [25]. The limited data warrants further investigation. The paper also describes the role of T helper cells (Th1, Th2, Th17), regulatory T cells (Tregs), and the role of cytokines such as IL-10 and IL-6 in the inflammatory response associated with COVID-19.

The paper extensively reviews the existing literature on T cell responses to SARS-CoV-2, encompassing various aspects from the initial stages of infection to the development of vaccines and the emergence of variants. Several studies cited demonstrate the correlation between robust T cell responses and milder COVID-19 outcomes, highlighting the critical role of cellular immunity in viral clearance. Conversely, the literature also points towards the potential for dysregulated T cell activation to contribute to severe disease through cytokine storms and immunopathology. The review delves into the complex interplay between different T cell subsets (CD4+, CD8+, Th1, Th2, Th17, Tregs) and their contribution to the overall immune response, drawing from multiple studies that analyzed the kinetics of T cell activation, cytokine profiles, and their association with disease severity. The analysis of T cell responses to various vaccines is also thoroughly discussed. The research papers reviewed explore the effectiveness of different vaccine platforms in inducing T cell immunity, its duration, and the impact of mutations in the SARS-CoV-2 spike protein on T cell recognition. The phenomenon of T cell exhaustion is another focal point, with studies illustrating its potential association with severe COVID-19 and its implications for long-term immunity. The review comprehensively surveys the literature on immune modulatory strategies and therapies being investigated to enhance T cell responses and mitigate T cell exhaustion, drawing insights from existing clinical trials and preclinical models. This comprehensive review is crucial for developing effective vaccines and therapies against the evolving SARS-CoV-2 virus.

This research paper employs a systematic review methodology. The authors conducted a comprehensive literature search across multiple databases to identify relevant studies investigating the T cell-mediated immune response to SARS-CoV-2 infection and vaccination. The search strategy likely included keywords related to SARS-CoV-2, COVID-19, T cells, immune response, cytokines, vaccines, variants, and T cell exhaustion. Inclusion and exclusion criteria were likely defined to select studies meeting specific quality standards, such as those published in peer-reviewed journals, focusing on human studies, and employing robust methodologies (e.g., flow cytometry, ELISpot assays). The selected publications were then systematically analyzed and synthesized to extract relevant data and insights on T cell responses during different stages of COVID-19 infection, across various SARS-CoV-2 variants, and post-vaccination. The authors likely critically appraised the quality of the included studies to assess their methodological rigor and potential biases. Data extraction focused on key variables such as T cell subset frequencies, cytokine profiles, disease severity, vaccine efficacy, and the occurrence of T cell exhaustion. The extracted data were then synthesized to develop a comprehensive overview of the T cell-mediated immune response to SARS-CoV-2. The authors have likely created detailed figures and tables to visually present the key findings and provide a structured summary of the reviewed literature. This rigorous methodology ensures a comprehensive and unbiased review of the current state of knowledge in the field.

The paper's key findings revolve around the complex and multifaceted role of T cells in the immune response to SARS-CoV-2 infection and the implications for vaccine development. It highlights the critical role of T cells in viral clearance and protection against severe disease. The review establishes a strong correlation between robust T cell responses (particularly early IFN-gamma production) and a favorable prognosis. Conversely, reduced T cell counts, T cell exhaustion, and hyperactivation are linked to more severe disease and poor outcomes. The study emphasizes the importance of various T cell subsets (Th1, Th2, Th17, Tregs) and their associated cytokines (e.g., IL-6, IL-10, IFN-gamma, TNF-alpha) in shaping the immune response and influencing disease progression. A key finding is the identification of T cell exhaustion as a significant factor in severe COVID-19, characterized by increased expression of inhibitory receptors (PD-1, CTLA-4, TIM-3) and reduced effector function. The research also underscores the relatively conserved nature of T cell epitopes across SARS-CoV-2 variants, suggesting the potential for existing vaccines to offer broad protection even against emerging variants. Despite variations in antibody responses, T cell-mediated immunity seems largely preserved, raising questions about the need for variant-specific vaccines. Several immunomodulatory therapies, including the use of immune checkpoint inhibitors (e.g., anti-PD-1 antibodies), and the modulation of cytokine levels (e.g., IL-6 blockade), are identified as potential strategies to enhance T cell function, reverse T cell exhaustion, and mitigate the severity of COVID-19. Finally, the paper highlights the need for standardized methods to measure and monitor T cell responses to accurately assess immune status in individuals and populations.

The findings significantly advance our understanding of the T cell-mediated immune response to SARS-CoV-2, addressing the limitations of previous research by integrating data from multiple studies across diverse SARS-CoV-2 variants. The identification of T cell exhaustion as a key factor in severe COVID-19 highlights new therapeutic targets and avenues for intervention. The relative conservation of T cell epitopes across variants suggests existing vaccines might offer broader protection than initially anticipated, although ongoing monitoring of variant-specific immune evasion remains crucial. The discussion of immunomodulatory strategies offers a roadmap for future therapies, particularly the investigation of immune checkpoint inhibitors and targeted cytokine modulation. The paper's emphasis on the need for standardized T cell response assessment methods is particularly timely and highlights the importance of collaborative research efforts to ensure reliable data comparison and informed decision-making in managing the pandemic. These findings are relevant to vaccine development and therapeutic strategies, informing the design of more effective vaccines and therapies to combat the evolving SARS-CoV-2 virus and future viral outbreaks.

This comprehensive review consolidates current knowledge on the T cell-mediated immune response to SARS-CoV-2, emphasizing its critical role in determining disease severity and the potential of immunomodulatory therapies. While existing vaccines induce broadly protective T cell responses, monitoring for T cell escape from emerging variants remains vital. Future research should focus on dissecting the intricate interplay between specific T cell subsets, cytokines, and disease pathogenesis to refine therapeutic interventions, particularly those targeting T cell exhaustion. Standardization of T cell response assessment methods will be essential for tracking immune status and evaluating the efficacy of future vaccines and therapies.

While this review integrates a significant body of research, certain limitations should be considered. The included studies might not represent the full diversity of COVID-19 cases globally, potentially introducing bias due to geographical, demographic, or healthcare system variations. The heterogeneity of methodologies across the reviewed studies might also limit direct comparisons and necessitate cautious interpretation of some findings. The rapid pace of SARS-CoV-2 evolution means any conclusions regarding variant-specific immunity might be subject to change as new variants emerge. Future research with standardized protocols and larger, more diverse cohorts will be essential to strengthen the conclusions presented in this review.