What are the unresolved questions about SARS-CoV-2 T-cell responses?

By Samantha Black, PhD, The Science Advisory Board editor in chief

November 18, 2020 -- Researchers have shed light on the "known unknowns" of preexisting and acquired T-cell responses in relation to SARS-CoV-2 infection. In a perspective piece, published in Science Immunology on November 18, scientists from Karolinska Institutet in Sweden discuss the role and durability of T-cell responses in COVID-19.

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 regarding T-cell immunity against respiratory viral infections.

Are T cells in the blood indicative of lung-specific responses in acute SARS-CoV-2?

First, although T-cell activation plays a role in dampening disease severity, there are other reports detailing dysregulated and unchecked T-cell activation leading to severe cases of SARS-CoV-2 infection. Increased T-cell activation may reflect increased 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 resolve this question.

One way that scientists may be able to confirm this hypothesis is through detection of T-cell activation in the blood. Therefore, it is important to define if T-cell activation in the blood correlates with 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 seems to be associated with disruption of T- and B-cell coordination and thus more severe disease. Alternatively, pediatric patients have reduced CD4+ T cells, which has been associated with shorter hospital stays. Females appear to mount a somewhat stronger T-cell activation in response to SARS-CoV-2 compared to men.

From a molecular point of view, SARS-CoV-2 infection causes a surge of proinflammatory signals including type I interferons -- directly influencing the early expansion and differentiation of antiviral T cells – that may lead to delayed clearance of SARS-CoV-2. According to the authors, it is tempting to say that higher risk elderly individuals experience delayed activation of SARS-CoV-2-specific T cells that leads to reduced viral clearance and more severe disease. They state that more data is needed to understand the specific mechanisms underlying these factors.

What types of memory T cells are formed in response to SARS-CoV-2?

Both SARS-CoV-2-specific CD4+ and CD8+ T cells have been detected in blood samples from convalescent donors. Effector CD4+ T cells (activated) usually possess Th1 or circulating T follicular helper (TFH) cell phenotypes. Th1 CD4+ T cells lead to increased cell-mediated immune responses and the formation of memory T cells. TFH are antigen experienced CD4+ T cells found within B-cell follicles to mediate the formation of memory B cells. On the other hand, CD8+ T cells (or killer T cells) are lymphocytes that target antigen-specific activated cells (or cells infected with virus). It is well established that CD4+ T cells recirculate between tissues and blood at a much higher rate than CD8+ T cells.

In postmortem examination, the TFH phenotype seems 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 declining antibody responses in convalescent donors. The authors also question if 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. Preexisting SARS-CoV-2-specific T cells may allow a host to bypass immune evasion mechanisms and generate early pressure on the virus, said the authors.

Resident memory T cells reside within tissues and do not recirculate to peripheral blood. There is a growing body of literature that suggests that resident memory T cells can provide protection against severe pulmonary disease. The authors stated that 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 also needs to be done to determine if resident memory T cells are short-lived, as there is conflicting evidence on their lifespan.

What type of T-cell responses elicited by vaccines will be the best predictor of protection from disease following exposure to the virus?

Many ongoing vaccine efforts mainly target B cells to promote the induction of neutralizing antibodies against SARS-CoV-2. However, the authors stated that T cells, specifically TFH cells, are critical to generate antibody-producing plasma cells and long-lived memory B cells. They suggest that future vaccine trials should include other activation induced markers (besides those for Th1) such as CD40L and CD200 in addition to IFN-γ enzyme-linked immune absorbent spot (ELISpot) assays to understand if potent B-helper mechanisms are induced by the current vaccine regimens.

Filling these gaps in knowledge using both animal models and longitudinal studies in large patient cohorts is vital for the formulation of effective COVID-19 vaccines and treatments.

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