The role of SARS-CoV-2-specific T cells induced by infection, vaccination, or their combination in protection against the disease

In a recent study published in the journal Immunity, researchers assessed how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cells induced by infection, vaccination, or both conferred protection against severe coronavirus disease 2019 (COVID-19 ). Additionally, they assessed the role of six epidemiological and virological variables affecting the functioning of SARS-CoV-2-specific T cells.

Study: SARS-CoV-2-specific T cells in the changing landscape of the COVID-19 pandemic. Image Credit: Juan Gaertner/Shutterstock


Previous correlates of protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have focused primarily on humoral immunity. However, attention has shifted to the correlates of protection against disease, which involves comprehensive analysis of cellular and humoral immunity.

About the study

In the current study, the researchers summarized the significant SARS-CoV-2-specific T cell responses seen in those vaccinated, infected, or who developed hybrid immunity after a breakthrough infection post-vaccination. The study presented six broad determinants (variables) of SARS-CoV-2-specific T cell responses that provided protection against COVID-19.

These were the composition, localization, specificity, cross-reactivity of T cells, their antigenic extent and associated hierarchies of protection against disease, and the magnitude of lymphocyte-mediated immune responses T. Additionally, they investigated how these six variables have changed with the continuously changing epidemiological, virological, and immunological landscape throughout the COVID-19 pandemic.

Study results

The study described two major subsets of SARS-CoV-2-specific T cells, including the differentiating cluster (CD)8+ and CD4+ T cells, their anatomical niche (location) and the viral antigen(s) targeted by each T cell subset (specificity).

Using their specific T-cell receptors (TCRs), CD8+ T cells detected host cells that harbored replicating SARS-CoV-2 virions. They recognize viral epitopes presented by major histocompatibility complex (MHC) class I molecules. Let CD8+ cells directly lyse infected cells or release cytokines [e.g., interferon-gamma (IFN-γ)] to fight the virus. Likewise, CD4+ 4 T cells can directly recognize and lyse SARS-CoV-2 infected cells. However, their activation requires epitopes derived from the processing of viral proteins internalized by host antigen-presenting cells (APCs), such as dendritic cells (DCs) and presented by MHC class II molecules. naïve CD4+ T cells also develop T helper 1 (Th1), Th2, Th17 cells, regulatory T cells (Treg) and follicular helper T cells (Tfh).

Several research groups have collectively detected SARS-CoV-2-specific T cell subpopulations in COVID-19 convalescents and asymptomatic patients (who did not seroconvert). Sette and Crotty’s research groups have shown a coordinated immune response including humoral and cellular immunity to SARS-CoV-2 and its correlation with recovery from infection without progression to severe disease.

Preliminary studies have supported the idea that T cells contribute significantly to protection against COVID-19. For example, Tan et al. showed that patients with prolonged infection and severe COVID-19 mounted robust antibody responses but had undetectable circulating SARS-CoV-2-specific T cells. Subsequent longitudinal studies performed in mild/severe patients by Tarke et al. confirmed these findings. Studies have also subsequently characterized the impact of COVID-19 vaccine-induced T cell responses. Zhang et al. published a comparative analysis of the T- and B-cell immunogenicity of messenger ribonucleic acid (mRNA), adenovirus, and protein-based COVID-19 vaccines. Research by Lim et al. collection of similar data for inactivated virus vaccines is ongoing.

Vaccination against COVID-19 does not attenuate the induction of a broader repertoire of SARS-CoV-2-specific T cells at the initial site of infection. Therefore, Lim et al. different recognized epitopes nested inside non-SARS-CoV-2 spike (S) proteins, similar to what Minervina et al. detected in the circulatory compartment. According to Wellington et al., there was no defined hierarchy of SARS-CoV-2 proteins that could generate CD8-triggering epitopes+ and CD4+ T cells with better protective efficacy. However, studies have asserted that the antigen-related hierarchy of protection is not related to the architecture of the assembled virion.

A recent report by McMenamin et al. demonstrated the efficacy of inactivated virus-based COVID-19 vaccines in reducing disease severity during the recent wave of Omicron infection in Hong Kong. Indeed, the breath of a CD4-specific multi-protein vaccine+ The T cell subpopulation could compensate for the absence of CD8+ T cells in attenuation of Omicron breakthrough infections.


An important takeaway from the current review is that CD8+ T cells and partially CD4+ T cells overlook crucial spatial information for an antibody in neutralizing viruses. Instead, they use epitopes derived from structural proteins found in the virus [like nucleocapsid (N)] or non-structural proteins (NSPs) in infected cells. Studies by Ferretti et al., Grifoni et al., and Le Bert et al., 2020 confirmed the robustness live the immunogenicity of SARS-CoV-2 NSPs despite their low quantity in infected cells, especially at the start of infection (six to 12 hours).

Moreover, most analyzes of the cellular (also humoral) immune response were previously confined to the circulatory compartment. However, recent work by Afkhami et al.; Ishii et al.; Mao et al., showed the protective value of specific induction of SARS-CoV-2-specific cellular immunity in the upper respiratory tract in infected mice vaccinated against SARS-CoV-2. Cheemarla et al. showed that the enrichment of T cells due to the high levels of chemokines secreted into the tissues was proportional to the replication of SARS-CoV-2 in humans.

To conclude, studies assessing the ability of human T cells to recognize SARS-CoV-2-infected cells and not peptide-pulsed cells are urgently warranted.

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