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Although many studies have shown that T cells play an important role in the early immune response to SARS-CoV-2 and can generate functional memory against the virus, there are still many questions about T cell immunity against respiratory viral infections.
Are blood T cells indicative of specific pulmonary responses in acute SARS-CoV-2?
First, although T cell activation plays a role in mitigating disease severity, there are other reports detailing dysregulated and uncontrolled T cell activation leading to severe cases of SARS infection. CoV-2. The increased activation of T lymphocytes may reflect an increase in antigen levels in the respiratory system. It has been hypothesized that in severe cases, early T-cell responses reach a state of exhaustion resulting in severe hyperinflammation, but more scientific evidence is needed to address this question.
One way scientists may be able to confirm this hypothesis is by detecting the activation of T lymphocytes in the blood. Therefore, it is important to define whether the activation of T cells in the blood is related to tissue-specific events, for example in the lungs.
What are the underlying cases of early and late onset of SARS-CoV-2 specific T-cell activity?
Based on the literature, old age appears to be associated with disruption of T and B cell coordination and therefore with more severe disease. Alternatively, pediatric patients have reduced CD4 + T cells, which has been associated with shorter hospital stays. Females appear to activate somewhat stronger T-cell activation in response to SARS-CoV-2 than males.
From a molecular point of view, SARS-CoV-2 infection causes a surge of proinflammatory signals including type I interferons – directly affecting the early expansion and differentiation of antiviral T cells – which can lead to clearance delayed by SARS-CoV-2. According to the authors, it is tempting to say that older individuals at higher risk experience delayed activation of SARS-CoV-2 specific T cells leading to reduced viral clearance and more severe disease. They say more data is needed to understand the specific mechanisms behind these factors.
What types of memory T cells are formed in response to SARS-CoV-2?
Both CD4 + and CD8 + T lymphocytes specific for SARS-CoV-2 were detected in blood samples from convalescent donors. Effector (activated) CD4 + T lymphocytes usually possess Th1 or circulating follicular helper T cell (TFH) phenotypes. Th1 CD4 + T cells lead to an increase in cell-mediated immune responses and the formation of memory T cells. TFHs are antigen-experienced CD4 + T cells that are found in B cell follicles to mediate memory B cell formation. On the other hand, CD8 + T cells (or killer T cells) are lymphocytes that target antigen-specific activated cells (or virus-infected cells). It is well known that CD4 + T cells recirculate between tissues and blood at a much faster rate than CD8 + T cells.
In post-mortem examination, the TFH phenotype appears to be impaired in patients with severe COVID-19. Further studies are needed to clarify whether TFH cell formation is impaired by SARS-CoV-2 and whether this could have an effect on decreased antibody responses in convalescent donors. The authors also question whether impaired development of SARS-CoV-2-specific memory T cells is linked to more severe COVID-19.
There has been some evidence that memory T cells formed in response to other coronaviruses could potentially cross-react with SARS-CoV-2 during infection. The ability of unexposed individuals to recognize SARS-CoV-2 peptides with the presence of CD4 + and CD8 + T cells may be due to a high level of amino acid similarity between SARS-CoV-2 epitopes and those of seasonal coronaviruses . Pre-existing SARS-CoV-2-specific T cells may allow a host to bypass immune evasion mechanisms and generate early pressure on the virus, the authors said.
Resident memory T lymphocytes reside within tissues and do not recirculate in peripheral blood. There is a growing body of literature suggesting that resident memory T cells may provide protection against severe lung disease. The authors said it is currently unknown whether cross-reactive resident memory T cells induced by seasonal coronaviruses can block transmission of SARS-CoV-2 from the upper respiratory tract to the lung to prevent disease. Research is also needed to determine whether resident memory T cells are short-lived, as there is conflicting evidence on their lifespan.
What kind of vaccine-induced T cell response will be the best predictor of disease protection following exposure to the virus?
Many ongoing vaccine efforts primarily target B cells to promote the induction of neutralizing antibodies against SARS-CoV-2. However, the authors stated that T cells, particularly TFH cells, are critical for generating antibody-producing plasma cells and long-lived memory B cells. They suggest that future vaccine trials should include other activation-induced markers (in addition to those for Th1) such as CD40L and CD200 in addition to ELISpot (IFN-γ enzyme-linked immunosorbent spot) tests to understand whether potent B-helper mechanisms are induced by current vaccination regimens.
Filling these knowledge gaps using both animal models and longitudinal studies in large patient cohorts is vital to formulating effective COVID-19 vaccines and treatments.
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