Human CD4+ T cells specific for dominant epitopes of SARS-CoV-2 Spike and Nucleocapsid proteins with therapeutic potential

Abstract

Since December 2019, Coronavirus disease-19 (COVID-19) has spread rapidly across the world, leading to a global effort to develop vaccines and treatments. Despite extensive progress, there remains a need for treatments to bolster the immune responses in infected immunocompromised individuals, such as cancer patients who recently underwent a haematopoietic stem cell transplantation. Immunological protection against COVID-19 is mediated by both short-lived neutralising antibodies and long-lasting virus-reactive T cells. Therefore, we propose that T cell therapy may augment efficacy of current treatments. For the greatest efficacy with minimal adverse effects, it is important that any cellular therapy is designed to be as specific and directed as possible. Here, we identify T cells from COVID-19 patients with a potentially protective response to two major antigens of the SARS-CoV-2 virus, Spike and Nucleocapsid protein. By generating clones of highly virus-reactive CD4+ T cells, we were able to confirm a set of 9 immunodominant epitopes and characterise T cell responses against these. Accordingly, the sensitivity of T cell clones for their specific epitope, as well as the extent and focus of their cytokine response was examined. Moreover, by using an advanced T cell receptor (TCR) sequencing approach, we determined the paired TCR sequences of clones of interest. While these data on a limited population require further expansion for universal application, the results presented here form a crucial first step towards TCR-transgenic CD4+ T cell therapy of COVID-19.

The T cell immune response against SARS-CoV-2

“…Indeed, over 1,400 potential epitopes have been identified so far 56,57 . Genomic regions of immunodominance are emerging, as are defined peptide epitopes that are commonly shared between donors 58 , including those within the receptor-binding domain (RBD) 59 . Moreover, immunodominant peptides may also be derived from out-of-frame open reading frame sequences that are not captured in current vaccine regimens 60,61 .…”

Mutations in SARS-CoV-2 spike protein impair epitope-specific CD4+ T cell recognition

“…SARS-CoV-2 CD4 + T cell epitopes have been identified, but mostly in assays that use high concentrations of stimulating peptides. In addition, their human leukocyte antigen (HLA) restriction has largely been inferred from in silico HLA-binding algorithms 11,12 . Detailed knowledge of the specificity of CD4 + T cell responses at the epitope level and their HLAII restriction is therefore currently lacking 13 .…”

Successful treatment of COVID‐19 infection with convalescent plasma in B‐cell‐depleted patients may promote cellular immunity

“…Moreover, we looked at the expression of the activation marker CD137 on CD4 + and CD8 + T cells after overnight restimulation in vitro with peptides that together span the lengths of SARS‐CoV‐2 S and N proteins. We previously found CD137 to be a good marker for T cells that recognize SARS‐CoV‐2 epitopes with high affinity [ 10 ]. In patient 1, CD38 + HLA‐DR + CD4 + and CD8 + T cells showed a remarkable increase after the first plasma administration but remained stable after the second dose (Fig.…”