From Alpha to omicron: The response of T cells

Abstract

It is critically important to understand how the adaptive immune response, elicited by vaccination or infection, recognizes SARS-CoV-2. This is especially true when considering the challenges to the immune response posed by variant evolution. Herein, we summarize our work aimed at characterizing the magnitude of the CD4⁺ and CD8⁺ T cell responses to SARS-CoV-2, the proteins most frequently recognized, and the associated T cell epitope repertoire. This work formed the foundation for our most recent studies aimed at understanding and predicting the ability of T cell responses induced by SARS-CoV-2 infection or vaccination to subsequently cross-recognize novel SARS-CoV-2 variants. We found that T cell responses are remarkably preserved and able to cross-recognize SARS-CoV-2 variants, from Alpha to Omicron. This is distinct from what has been observed for the SARS-CoV-2- specific antibody and B cell responses. This body of work, supported by independent studies carried out by other groups, suggests that T cells may contribute to a second line of defense against infection while also limiting viral spread and, thus, disease severity.

Keywords: CD4; CD8; SARS-CoV-2; Variants of concern.

Graphical abstract

Fig. 1

SARS-CoV-2 adaptive response. SARS-CoV-2 infection induces different arms of the adaptive immune response. B cells produce antibodies (Abs) able to prevent infection (neutralizing) or limit spreading (non-neutralizing). CD8⁺ and CD4⁺ T cells recognize infected cells and limit viral spreading by producing cytokines and cytotoxic molecules to kill the infected cells and by helping coordinate the different arms of the immune system.

Fig. 2

T cell protein immunodominance and epitope repertoire after SARS-CoV-2 infection or vaccination. T cell responses recognize up to 10 different SARS-CoV-2 proteins representing 80% or more of the overall response, with the spike (S) being the most immunodominant, followed by Nucleocapsid (N), Membrane (M), and other Non-structural proteins (Nsps). At the epitope level, 30-40 epitopes are recognized by either CD4⁺ or CD8⁺ T cells after natural infection considering all SARS-CoV-2 proteins recognized. A median of 10–11 epitopes are recognized specifically for S protein in natural infection similarly to what is observed after vaccination.

Fig. 3

T cell responses induced by SARS-CoV-2 natural infection or vaccination recognize SARS-CoV-2 variants. SARS-CoV-2 specific T cell responses induced after natural infection or vaccination with different vaccine platforms induce a SARS-CoV-2 ancestral-specific T cell response able to cross-recognize with a similar magnitude several SARS-CoV-2 variants of concern and interest, including omicron.

Fig. 4

Predicting the impact of emerging SARS-CoV-2 variants on T cell responses. List of known epitopes recognized by CD4⁺ and CD8⁺ T cells available in IEDB (www.IEDB.org) in combination with amino acid mutations related to a broad list of SARS-CoV-2 variants including variants of concern and interest. Analysis of the database revealed similarly high numbers of conserved epitopes and, conversely, low numbers of epitopes with variant-specific mutations, disregarding the variant mutations analyzed. Further, the majority of mutations in epitopes do not impact the ability of HLA molecules to present the epitope to T cells. Thus, the number of epitopes impacted by variants and the number of epitopes still recognized by the T cell response are likely to be higher than estimated.