Role of T cells in severe COVID-19 disease, protection, and long term immunity

The COVID-19 pandemic, caused by SARS-CoV-2, resulted in millions of deaths and infections. Research has identified risk factors for severe COVID-19, including age, sex, comorbidities, and the magnitude of initial innate immune responses (cytokine storm). While the role of cytokines and antibodies has been extensively studied, the contribution of T cells to COVID-19 severity and protection remains less understood. This is surprising given that the adaptive immune response, including T cells, is active before hospitalization and that risk factors for severe COVID-19 impact both innate and adaptive immunity. For example, poor CD8 T cell activation in males and higher innate immune cytokine levels in females were associated with worse outcomes. Understanding the role of T cells in COVID-19 is crucial for developing effective prevention and treatment strategies. This review will examine the role of T cells in disease severity, protection against severe disease upon reinfection, and the longevity of T cell immunity.

Existing research highlights the importance of antibodies in COVID-19 immunity, with current vaccines focusing on generating antibody responses against the spike (S) protein. However, antibody responses often wane over time, as observed in SARS-CoV-1, and their effectiveness against viral variants is significantly reduced. Studies on patients with X-linked agammaglobulinemia, who lack B cells but recovered from COVID-19, along with observations of SARS-CoV-2-specific T cell responses in seronegative individuals, suggest a crucial role for T cells in protection. This review will specifically investigate the long-term role of T cells in disease severity, recovery, and the development of effective vaccination strategies.

This review synthesizes current knowledge on the contribution of T cells in COVID-19 through a comprehensive analysis of existing literature. The review focuses on three key questions: 1. Do T cells contribute to or counteract disease progression? 2. Does T cell immunity protect against severe disease upon reinfection? 3. Is T cell immunity long-lasting? The review examines numerous studies on various aspects of T cell involvement in COVID-19, including the association between T cell counts and disease severity, the role of overactivated T cells in tissue damage, the generation and function of memory T cells (including circulating and tissue-resident memory T cells) after natural infection or vaccination, the impact of memory T cells on reinfection, and the longevity and cross-reactivity of SARS-CoV-2-specific T cell responses against different variants.

Lymphopenia, a reduction in T cell counts, is observed in hospitalized COVID-19 patients, particularly those with severe disease. An increase in CD8 T cells is associated with successful treatment. Lymphopenia may result from T cell relocation to inflamed lung tissue, cell death, or other mechanisms. Severe COVID-19 is associated with an enrichment of activated T cells (CD38+ HLA-DR+), possibly representing overactivated, exhausted, or apoptosis-sensitive cells. Early CD8 T cell responses appear protective, possibly through bystander activation and non-specific viral clearance, while a continuous rise in overactivated CD8 T cells is associated with severe disease and tissue damage. The overactivated T cells may contribute to tissue damage either through direct cytotoxic action or increased cytokine production. A superantigen-like motif in the SARS-CoV-2 spike protein might continuously activate T cells, leading to hyperinflammation. Following infection or vaccination, the body develops both circulating and tissue-resident memory T cells. The T cell response, particularly against the spike (S), membrane (M), and nucleocapsid (N) proteins, is broader and stronger in patients with severe COVID-19. Vaccination induces a T cell memory response comparable to natural infection, offering considerable protection against reinfection and severe disease. Memory T cell responses persist for at least eight months post-infection and appear relatively stable after an initial decline. The presence of long-lived stem memory T cells contributes to long-term immunity. Mutations in SARS-CoV-2 variants have a minimal impact on the overall T cell response, with most T cells still recognizing the variants, suggesting lasting immunity despite viral mutations.

The findings highlight the complex role of T cells in COVID-19. Early T cell responses appear protective, preventing disease progression, while later overactivation contributes to tissue damage. Both natural infection and vaccination induce long-lasting memory T cell responses that protect against severe disease and reinfection. The observed longevity and cross-reactivity of these T cell responses offer hope for long-term immunity, even with emerging variants. However, the precise protective effects of T cells in the absence of antibodies need further investigation, as well as the mechanisms of T cell overactivation and the precise role of bystander activation.

T cells play a critical role in protecting against severe COVID-19, preventing disease progression and offering long-term immunity. While overactivation can contribute to tissue damage, the overall protective effect of T cells suggests a hopeful outlook for post-pandemic life. Future research should focus on clarifying the roles of bystander activation, the interplay between innate and adaptive immunity in T cell activation and overactivation, and the specific protective effects of T cells in the absence of antibodies. Expanding vaccination strategies to include additional viral proteins like N and M might improve the breadth and longevity of T cell responses.

The current understanding of T cell dynamics in COVID-19 is still evolving. Many studies have limitations in sample size, disease severity stratification, and the precise timing of immune responses relative to infection onset. Further research, especially longitudinal studies with larger sample sizes and more precise tracking of infection timelines, is crucial to fully elucidate the protective and potentially damaging effects of T cells throughout the course of COVID-19.