Abstract
A central feature of the SARS-CoV-2 pandemic is that some individuals become severely ill or die, whereas others have only a mild disease course or are asymptomatic. Here we report development of an improved multimeric αβ T cell staining reagent platform, with each maxi-ferritin "spheromer" displaying 12 peptide-MHC complexes. Spheromers stain specific T cells more efficiently than peptide-MHC tetramers and capture a broader portion of the sequence repertoire for a given peptide-MHC. Analyzing the response in unexposed individuals, we find that T cells recognizing peptides conserved amongst coronaviruses are more abundant and tend to have a "memory" phenotype, compared to those unique to SARS-CoV-2. Significantly, CD8+ T cells with these conserved specificities are much more abundant in COVID-19 patients with mild disease versus those with a more severe illness, suggesting a protective role.
Highlights
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus causing COVID-19, has infected ∼120 million individuals worldwide, displaying a spectrum of disease severities that ranges from asymptomatic to life-threatening pneumonia and multi-organ failure [1]
In the search for a protein scaffold that could increase the valency of displayed pMHC and that would hopefully capture more αβ T cells of a given specificity, we focused on self-assembling homo-oligomers (Fig. S1A) [23, 24]
We evaluated viral-specific CD8+ T cells in healthy individuals to address the following questions: i) Does the spheromer detect a higher frequency of antigen-specific T cells than tetramer ex vivo? ii) How do the T cell receptor (TCR) repertoires detected by the spheromer and tetramer compare? We used immunodominant HLA-A*02:01 restricted epitopes for characterizing the spheromer since there is considerable data available for benchmarking [28]
Summary
CoV-2), the virus causing COVID-19, has infected ∼120 million individuals worldwide, displaying a spectrum of disease severities that ranges from asymptomatic to life-threatening pneumonia and multi-organ failure [1]. Addressing this global pandemic, many pharmaceutical companies and research laboratories have raced to develop effective coronavirus vaccines, of which over a hundred are in development [2]. The weak equilibrium dissociation constant (KD ∼1-200μM) between the TCR and monomeric pMHC results in a transient complex that impedes easy detection [15]. The detection of low affinity TCRs still remains challenging, partly due to an increased background from non-specific staining using higher valency platforms, negatively impacting the signal-to-noise ratio [19,20,21]
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