Can memory T cell responses to seasonal coronaviruses protect against severe COVID-19?

In a recent study published in the journal Science Immunology, scientists from Stanford University, USA, have revealed that the presence of CD8+ T cells against conserved epitopes of seasonal coronaviruses is associated with mild coronavirus disease 2019 (COVID-19). These immune cells exhibit a memory phenotype and provide protection against severe disease.


Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative pathogen of COVID-19, causes a wide variety of clinical manifestations, ranging from asymptomatic infection to severe life-threatening pneumonia, multiorgan failure, and death.

The majority of vaccines that have been developed to control the pandemic primarily aim to induce neutralizing antibodies against SARS-CoV-2 spike protein. However, studies investigating vaccine efficacy have shown diverse intensity and durability of vaccine-induced immune responses in the general population. This highlights the need for studying the involvement of T cell-mediated immunity in SARS-CoV-2 infection.

In humans, the majority of T cells express µβ T cell receptors to recognize a particular peptide that is attached to the major histocompatibility complex (MHC) molecule on target cells. The T cell receptor forms a transient complex with the monomeric peptide – MHC molecule (pMHC). Because of this weak interaction, it has become challenging to detect low-affinity T cell receptors.

To overcome this difficulty, the scientists in the current study have developed a biotinylation site on maxi-ferritin to create a 24-subunit nanoparticle scaffold for the multivalent display of pMHC. In this improved platform, each maxi-ferritin “spheromer” displays 12 pMHC, making it easier to detect and stain a wide range of antigen-specific T cell receptor repertoire more efficiently.

To develop a stable scaffold, they have derived ferritin from the hyperthermophilic archaeal anaerobe Pyrococcus furiosus. The major advantages of the “spheromer” staining platform include effortless production, low inter-batch variability because of site-specific conjugation of pMHC molecules, and compatibility with currently available pMHC molecules and other reagents.

Using this platform, they have studied SARS-CoV-2 specific CD8+ T cell response ex vivo.  

Important observations

In-depth characterization of the T cell staining platform revealed that the spheromer binds to both class I and class II MHC restricted T cells with high avidity and specificity. Moreover, it provided a better signal-to-noise ratio and detected a wide variety of antigen-specific T cell receptor repertoire.

The characterization of the spheromer was done using major antigens of influenza virus (M1 epitope) and human cytomegalovirus (pp65 epitope). Specifically, the spheromer platform was compared with the conventional pMHC-tetramer platform, in which four pMHC molecules are conjugated to streptavidin.

The staining of healthy donor-derived CD8+ T cells revealed that for both M1 and pp65 epitopes, the spheromer detected significantly higher frequencies of CD8+ T cells than the tetramer. Furthermore, paired αβ-TCR sequencing of spheromer+ CD8+ T cells revealed that the spheromer efficiently detected a much more diverse T cell receptor repertoire than the tetramer.

The specificity of spheromer-derived T cell receptor sequences was determined by an algorithm that clusters T cell receptors with similar antigen specificity. The findings revealed that the spheromer has high specificity for T cells restricted by both classes I and II MHC molecules. Further experiments with T cell lines expressing MHC-I or MHC-II restricted T cell receptors revealed that spheromer-detected T cell receptors bind to their cognate pMHC molecules with 30-fold lower affinity. This highlights the significance of spheromer in identifying low-affinity antigen-specific T cells.

Detection of T cell response in SARS-CoV-2 infection

According to available literature, more than 50% of viral epitope-specific T cells exhibit a memory phenotype, which in turn correlates significantly with protection against particular viral infections.

To evaluate T cell-mediated immunity in SARS-CoV-2 infection, CD8+ T cell frequencies were determined against a set of SARS-CoV-2 epitopes in both unexposed individuals and COVID-19 patients. In unexposed individuals, an elevated frequency of CD8+ T cells was observed against a few SARS-CoV-2 epitopes. Specifically, a higher frequency of CD8+ T cells was observed against the epitopes conserved across common cold-causing human coronaviruses than that against epitopes unique to SARS-CoV-2. Moreover, most of these T cells exhibited a memory phenotype.

The analysis of CD8+ T cell frequency against SARS-CoV-2 epitopes in COVID-19 patients revealed a significantly higher T cell response to conserved epitopes in patients with mild COVID-19. In contrast, patients with severe COVID-19 exhibited a higher T cell response to SARS-CoV-2 specific epitopes.

Taken together, these observations indicate that previous exposure to seasonal coronaviruses leads to the generation of memory CD8+ T cells specific for conserved epitopes. During SARS-CoV-2 infection, a preferential recruitment of these memory T cells provides protection against severe COVID-19.

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