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Review
. 2021 Jan;162(1):30-43.
doi: 10.1111/imm.13262. Epub 2020 Oct 27.

T-cell responses and therapies against SARS-CoV-2 infection

Salman M Toor  1 , Reem Saleh  1 , Varun Sasidharan Nair  1 , Rowaida Z Taha  1 , Eyad Elkord  1   2
Affiliations
Review

T-cell responses and therapies against SARS-CoV-2 infection

Salman M Toor et al. Immunology. 2021 Jan.

Abstract

Coronavirus disease 2019 (COVID-19) is caused by SARS-CoV-2, a novel coronavirus strain. Some studies suggest that COVID-19 could be an immune-related disease, and failure of effective immune responses in initial stages of viral infection could contribute to systemic inflammation and tissue damage, leading to worse disease outcomes. T cells can act as a double-edge sword with both pro- and anti-roles in the progression of COVID-19. Thus, better understanding of their roles in immune responses to SARS-CoV-2 infection is crucial. T cells primarily react to the spike protein on the coronavirus to initiate antiviral immunity; however, T-cell responses can be suboptimal, impaired or excessive in severe COVID-19 patients. This review focuses on the multifaceted roles of T cells in COVID-19 pathogenesis and rationalizes their significance in eliciting appropriate antiviral immune responses in COVID-19 patients and unexposed individuals. In addition, we summarize the potential therapeutic approaches related to T cells to treat COVID-19 patients. These include adoptive T-cell therapies, vaccines activating T-cell responses, recombinant cytokines, Th1 activators and Th17 blockers, and potential utilization of immune checkpoint inhibitors alone or in combination with anti-inflammatory drugs to improve antiviral T-cell responses against SARS-CoV-2.

Keywords: COVID-19; SARS-CoV-2; T cells; coronavirus; immune responses.

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Figures

Figure 1
Figure 1
T‐cell responses against SARS‐CoV‐2. SARS‐CoV‐2 recognizes cells expressing ACE2 receptor including epithelial cells and macrophages. In normal immune environment, infected epithelial cells degrade viral particles and present them to cytotoxic CD8+ T cells (CTLs). CTLs detect viral protein through classical TCR‐MHC I interaction, release cytotoxic granules, including granzyme B and perforin, and eliminate infected cells. Additionally, macrophages detect SARS‐CoV‐2 via ACE2 receptor and present the virus‐derived peptides to CD4+ T cells (Th0) via TCR‐MHC II interaction. Once exposed to antigen, Th0 cells polarize primarily towards Th1, leading to the release of IFN‐γ to eliminate the virus, and Th2 to trigger humoral‐mediated immune responses and antibody secretion against SARS‐CoV‐2 virus (A). In incompetent immune environment, SARS‐CoV‐2 recognizes epithelial cells or macrophages via ACE2 receptor. Viral RNA will replicate by hijacking the host transcriptional machinery. These viral progenies will infect multiple cells leading to tissue damage and further lethal complications. In these circumstances, CD4+ and CD8+ T cells fail to provide adequate cell/humoral‐mediated immune responses to eliminate viral‐infected cells. On the other hand, Th0 cells are primed towards Th17 phenotype, resulting in the inhibition of Th1‐mediated immune responses (B). In COVID‐19, T cells could be exhausted and could overexpress exhaustion markers including PD‐1, CTLA‐4, TIM‐3 and TIGIT through unknown mechanisms . In severe COVID‐19 cases, the production of cytokines, including IL‐1β, IL‐6, IL‐2, IL‐10 and TNF‐α, is increased leading to the generation of cytokine storm, which induces further unfavourable outcomes and may eventually lead to lymphopenia (B).
Figure 2
Figure 2
Therapeutic strategies to restore SARS‐CoV‐2‐specific T‐cell immune responses. Autologous (from a COVID‐19 patient) or allogeneic (from a recovered patient), peripheral blood mononuclear cells (PBMCs) can be cultured in the presence of SARS‐CoV‐2‐derived peptides, IL‐2, GM‐CSF or possibly other cytokines to enhance the function of antigen‐presenting cells, enrich T cells and enhance the generation of activated viral‐specific T cells, which can be infused back into a COVID‐19 patient. This could restore effective antiviral T‐cell immunity, and result in beneficial clinical outcomes (A). The use of viral vector‐based, mRNA‐based or DNA‐based vaccines expressing the S protein of SARS‐CoV‐2 can lead to the activation of virus‐specific CD4+ and CD8+ T cells via antigen‐presenting cells, followed by the activation of B cells and secretion of antibodies by plasma cells (B). In COVID‐19 patients, the administration of recombinant IL‐7 could enhance T‐cell receptor repertoire diversity, promote the capacity of T‐cell trafficking to the lungs and alleviate lymphopenia leading to enhanced antiviral immune response. Low‐dose recombinant IL‐2 could control ARDS and excessive inflammation by expanding and activating Tregs, and possibly increase the level of effector CD4+ and CD8+ T cells as they express IL‐2 receptor. Additionally, administration of interferons could also help in viral clearance and improving antiviral T‐cell responses (C).
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