Updated Insights into the T Cell-Mediated Immune Response against SARS-CoV-2: A Step towards Efficient and Reliable Vaccines

Abstract

The emergence of novel variants of SARS-CoV-2 and their abilities to evade the immune response elicited through presently available vaccination makes it essential to recognize the mechanisms through which SARS-CoV-2 interacts with the human immune response. It is essential not only to comprehend the infection mechanism of SARS-CoV-2 but also for the generation of effective and reliable vaccines against COVID-19. The effectiveness of the vaccine is supported by the adaptive immune response, which mainly consists of B and T cells, which play a critical role in deciding the prognosis of the COVID-19 disease. T cells are essential for reducing the viral load and containing the infection. A plethora of viral proteins can be recognized by T cells and provide a broad range of protection, especially amid the emergence of novel variants of SARS-CoV-2. However, the hyperactivation of the effector T cells and reduced number of lymphocytes have been found to be the key characteristics of the severe disease. Notably, excessive T cell activation may cause acute respiratory distress syndrome (ARDS) by producing unwarranted and excessive amounts of cytokines and chemokines. Nevertheless, it is still unknown how T-cell-mediated immune responses function in determining the prognosis of SARS-CoV-2 infection. Additionally, it is unknown how the functional perturbations in the T cells lead to the severe form of the disease and to reduced protection not only against SARS-CoV-2 but many other viral infections. Hence, an updated review has been developed to understand the involvement of T cells in the infection mechanism, which in turn determines the prognosis of the disease. Importantly, we have also focused on the T cells' exhaustion under certain conditions and how these functional perturbations can be modulated for an effective immune response against SARS-CoV-2. Additionally, a range of therapeutic strategies has been discussed that can elevate the T cell-mediated immune response either directly or indirectly.

Keywords: COVID-19; SARS-CoV-2; T cells; T-cells’ exhaustion; Therapeutics; immune response; vaccines.

Figure 1

The schematic representation of the integrated adaptive and innate immune responses that result in the elimination of the viral infection. The virus enters individuals following contact with the upper respiratory tract. After virus entrance, viral replication starts by attaching to ACE2 receptors on the membrane of diverse cell types. Antigen-presenting cells (APCs), including dendritic cells and alveolar macrophages, endocytose and destroy the SARS-CoV-2 virus via a procedure termed antigen processing. Antigen segments are subsequently expressed on the cell membrane by MHC proteins, allowing T cells to recognize them. Following the interaction with T cells like CD4+ and CD8+, different types of responses occur. When CD4+ cells interact with the presented antigen on the MHC class I molecule, the activation of B-cells occurs. This will lead to the clonal expansion of CD4+ cells and B cells. After eliciting the B cells with the help of CD4+ cells, secretion of the antibodies occurs, which clears the viral infection. Upon interaction with the CD8+ T cell, clonal expansion of T cells occurs, which leads to the apoptosis of the infected cells through various mechanisms and leads to the release of other pro-inflammatory mediators.

Figure 2

The association of the T cells with the excessive release of cytokines, disease severity, and ARDS. The expression of the ACE2 receptor on lymphocytes, particularly T cells, facilitates SARS-CoV-2 entrance into lymphocytes. During a mild infection or low viral load, the T cell number remains normal, and possibly normal functioning of the Th2 type cells will not lead to excessive inflammation and normal clonal expansion of T cells. However, under the severe form of the infection, monocyte accumulation and excessive antigen presentation lead to an increase in pro-inflammatory cytokine levels concurrently, causing T cell depletion and fatigue. Importantly excessive activation of Th1 and Th17 type T cells lead to increased levels of cytokines, importantly IL-6. Severe infection causes lymphopenia by directly affecting lymphatic organs such as the spleen and lymph nodes. The further figure represents various pathways for the excessive release of cytokines. Firstly, CD4+ T cells may be stimulated quickly into Th1 cells that secrete GM-CSF, generating CD14+CD16+ monocytes with high IL-6 levels. Secondly, an increase in the CD14+ IL-1+ monocyte subpopulation stimulates the production of IL-1. Additionally, Th17 cells generate IL-17, which recruits more monocytes, macrophages, and neutrophils while also stimulating other cytokine cascades, such as IL-1 and IL-6. This can lead to tissue damage and excessive accumulation of fluid in the lung, which in turn leads to multiple organ damage.

Figure 3

T-cell exhaustion and associated repercussions. Because of persistence antigen exposure and chronic T cell receptor (TCR) signalling, T cell exhaustion or dysregulation is common in severe viral infections. Exhausted T cells have lower proliferation and differentiation rates. Additionally, exhausted CD8+ T cells show reduced cytotoxic activities, altered gene expression, and dysfunctional metabolic activities. The dysfunctional mitochondria are also a key feature of exhausted T cells. Importantly, enhanced and persistent expression of several inhibitory receptors, notably PD-1, PDL-1, CTLA-4, CD39, and Tim-3, is a crucial factor of exhausted T cells. However, under steady-state conditions, these inhibitory receptors, also referred to as immune checkpoint proteins, are reversibly generated on activated lymphocytes and play a key role in regulating immunological balance by limiting the duration and intensity of T-cell responses. The transcription of all these receptors remains high in the exhausted T-cell state, while T-cell function diminishes, hindering effective viral elimination. Exhausted T cells release a variety of cytokines, including IFN-gamma, TNF-alpha, and IL-2, which may inhibit T-cell clonal growth and B-cell priming. As a result, all of these factors contribute to a weakened adaptive immune response. Several human mAbs have been developed to counteract these immune checkpoints to restore the T cells’ functionality even under the severe form of the disease.