The Robustness of Cellular Immunity Determines the Fate of SARS-CoV-2 Infection

Abstract

Two years after the appearance of the SARS-CoV-2 virus, the causal agent of the current global pandemic, it is time to analyze the evolution of the immune protection that infection and vaccination provide. Cellular immunity plays an important role in limiting disease severity and the resolution of infection. The early appearance, breadth and magnitude of SARS-CoV-2 specific T cell response has been correlated with disease severity and it has been thought that T cell responses may be sufficient to clear infection with minimal disease in COVID-19 patients with X-linked or autosomal recessive agammaglobulinemia. However, our knowledge of the phenotypic and functional diversity of CD8+ cytotoxic lymphocytes, CD4+ T helper cells, mucosal-associated invariant T (MAIT) cells and CD4+ T follicular helper (Tfh), which play a critical role in infection control as well as long-term protection, is still evolving. It has been described how CD8+ cytotoxic lymphocytes interrupt viral replication by secreting antiviral cytokines (IFN-γ and TNF-α) and directly killing infected cells, negatively correlating with stages of disease progression. In addition, CD4+ T helper cells have been reported to be key pieces, leading, coordinating and ultimately regulating antiviral immunity. For instance, in some more severe COVID-19 cases a dysregulated CD4+ T cell signature may contribute to the greater production of pro-inflammatory cytokines responsible for pathogenic inflammation. Here we discuss how cellular immunity is the axis around which the rest of the immune system components revolve, since it orchestrates and leads antiviral response by regulating the inflammatory cascade and, as a consequence, the innate immune system, as well as promoting a correct humoral response through CD4+ Tfh cells. This review also analyses the critical role of cellular immunity in modulating the development of high-affinity neutralizing antibodies and germinal center B cell differentiation in memory and long-lived antibody secreting cells. Finally, since there is currently a high percentage of vaccinated population and, in some cases, vaccine booster doses are even being administered in certain countries, we have also summarized newer approaches to long-lasting protective immunity and the cross-protection of cellular immune response against SARS-CoV-2.

Adaptive immunity to SARS-CoV-2 infection: A systematic review

“…Expression of the CCL3/4/5 gene (MIP-1s) and the CXCL1 chemokine, which is exclusive to CD4+ T cells, may aid in effector cell recruitment. Increased apoptosis and decreased T cell proliferation rates may be the causes of the decrease in T cells in COVID-19, or they may both be contributing factors ( 25 , 40 , 63 ).…”

“…Polyclonal T-cell activation is also a risk factor that causes a decrease in the production of certain cytokines together with terminal differentiation in patients ( 27 ). SARS-CoV-2 positive B and T cells from working memory were found 12 months after the first natural infection ( 63 ).…”

Progressive loss of conserved spike protein neutralizing antibody sites in Omicron sublineages is balanced by preserved T-cell recognition epitopes

“…In the face of this highly dynamic situation, we have set up a COVID-19 pandemic preparedness and rapid response strategy. Our approach includes the screening of emerging and circulating variants through an artificial intelligence/machine learning-based early warning system ( 13 ), testing prototypical mRNA vaccines adapted to these variants in mouse studies ( 16 ), and mapping SARS-CoV-2 T-cell epitopes recognized by the human T-cell repertoire ( 19, 20 ). Further, studying the neutralizing antibody activity of individuals following breakthrough infections with the latest circulating variants allows us to detect potential immune escape patterns early and informs on the need for rapid vaccine adaptation strategies ( 14–18 ).…”

“…In the face of this highly dynamic situation, we have set up a COVID-19 pandemic preparedness and rapid response strategy. Our approach includes the screening of emerging and circulating variants through an artificial intelligence/machine learning-based early warning system (13), testing prototypical mRNA vaccines adapted to these variants in mouse studies (16), and mapping SARS-CoV-2 T-cell epitopes recognized by the human T-cell repertoire (19,20).…”

COVID-19 in kidney transplantation-implications for immunosuppression and vaccination

“…Cellular immunity is an important arm of the immune system and can be measured by (SARS-CoV-2)-specific, interferon-γ (IFN-γ)-producing T and B cells, measured with an enzyme-linked immunospot (ELISpot) assay ( 12 – 14 ). Interferon gamma release assay (IGRA) is a measure of T cell response and is performed by isolating peripheral blood mononuclear cells (PBMCs) from subjects after vaccination.…”