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

By Neha MathurReviewed by Danielle Ellis, B.Sc.Aug 24 2022

In a recent study published in the journal Immunity, researchers evaluated how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific-T lymphocytes 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 impacting the functioning of SARS-CoV-2-specific T cells.

Background

Earlier correlates of protection from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection mainly focused on humoral immunity. However, the focus has shifted to correlates of protection from disease, which involves a comprehensive analysis of both cellular and humoral immunity.

About the study

In the present study, researchers summarized significant SARS-CoV-2-specific T cell responses observed in individuals who were vaccinated, infected, or had developed hybrid immunity following breakthrough infection after vaccination. The study laid out six broad determinants (variables) of SARS-CoV-2-specific T cell responses that mediated protection against COVID-19.

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

Study findings

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

Utilizing their specific T cell receptors (TCR), 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. Either CD8⁺ cells directly lysed infected cells or released cytokines [e.g., interferon-gamma (IFN-γ)] to combat the virus. Similarly, CD4⁺ 4 T cells can recognize and directly 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 the MHC class II molecules. Naïve CD4⁺ T cells also develop T helper 1 (Th1), Th2, Th17, regulatory T cells (Treg), and T follicular helper (Tfh) cells.

Several research groups have collectively detected SARS-CoV-2-specific-T cell sub-populations in COVID-19 convalescents and asymptomatic patients (who did not seroconvert). The research groups of Sette and Crotty showed a coordinated immune response comprising SARS-CoV-2 humoral and cellular immunity and its correlation with recovery from infection without progression to severe illness.

Preliminary studies supported the notion that T cells contribute substantially to protection against COVID-19. For instance, 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 work by Lim et al. to gather similar data for inactivated virus vaccines is underway.

COVID-19 vaccination does not subdue the induction of a broader SARS-CoV-2-specific T cell repertoire at the initial infection site. Consequently, Lim et al. recognized different epitopes nested inside the 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 the SARS-CoV-2 proteins that might generate epitopes triggering CD8⁺ and CD4⁺ T cells with better protective efficiency. However, studies have affirmed that the antigen-linked protection hierarchy is unrelated to the architecture of the assembled virion.

A recent report by McMenamin et al. demonstrated the effectiveness of inactivated virus-based COVID-19 vaccines in reducing disease severity in the recent Omicron infection wave in Hong Kong. Indeed, the breath of a vaccine-induced multi-protein specific CD4⁺ T cell sub-population might compensate for the absence of CD8⁺ T cells in mitigating Omicron breakthrough infections.

Conclusions

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

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

To conclude, studies that evaluate human T cells' ability to recognize SARS-CoV-2-infected cells and not peptide-pulsed cells are urgently warranted.