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.

Keywords: COVID-19; SARS-CoV-2; cellular immunity; cytotoxic T lymphocytes; evasion; helper T cells; severity; vaccine.

Figure 1

Cellular immune response in Mild COVID-19. In mild COVID-19, there is an early induction of the Th1 cell-biased phenotype with IFN-γ secreting SARS-CoV-2-specific T cells. In turn, SARS-CoV-2-specific CD8+ T cells perform rapid responses, acting as CTLs, secreting cytotoxic granules and high levels of IFN-γ. Moreover, activated Tfh cells in the draining lymph nodes activate the naïve B cells that are necessary for the development of long-lived plasma cells and memory B cells. Cellular immune response in Severe COVID-19. During a severe course of COVID-19, there are reduced numbers and functions of DCs, leading to decreased numbers of CD4+ T cells. In this case, an elevation of Th2 phenotype and/or a dysregulation of the Treg/Th17 cell ratio toward the Th17 phenotype can be seen. Furthermore, decreased numbers of CD8+ T cells with an exhausted phenotype results in reduced CTL functionality while the T cell-mediated activation of B cells in extrafollicular focus induces their differentiation into short-lived plasma cells.

Figure 2

Parameters to be assessed regarding humoral and cellular response to SARS-CoV-2 mRNA vaccine. The top and middle figure outline the immunological response achieved after the first and second doses of mRNA vaccines, respectively. The bottom figure summarizes the parameters needed to assess protection against SARS-CoV-2.