Induction of Antiviral T Cell Responses
Available information about SARS-CoV-1-specific T cell immunity may serve as an orientation for further understanding of SARS-CoV-2 infection. Immunogenic T cell epitopes are distributed across several SARS-CoV-1 proteins (S, N, and M, as well as ORF3), although CD4 T cell responses were more restricted to the S protein (Li et al., 2008). In SARS-CoV-1 survivors, the magnitude and frequency of specific CD8 memory T cells exceeded that of CD4 memory T cells, and virus-specific T cells persisted for at least 6–11 years, suggesting that T cells may confer long-term immunity (Ng et al., 2016, Tang et al., 2011). Limited data from viremic SARS patients further indicated that virus-specific CD4 T cell populations might be associated with a more severe disease course, since lethal outcomes correlated with elevated Th2 cell (IL-4, IL-5, IL-10) serum cytokines (Li et al., 2008). However, the quality of CD4 T cell responses needs to be further characterized to understand associations with disease severity. Few studies have thus far characterized specific T cell immunity in SARS-CoV-2 infection. In 12 patients recovering from mild COVID-19, robust T cell responses specific for viral N, M, and S proteins were detected by IFN-γ ELISPOT, weakly correlated with neutralizing antibody concentrations (similar to convalescent SARS-CoV-1 patients; Li et al., 2008), and subsequently contracted with only N-specific T cells detectable in about one-third of the cases post recovery (Ni et al., 2020). In a second study, PBMCs from COVID-19 patients with moderate to severe ARDS were analyzed by flow cytometry approximately 2 weeks after ICU admission (Weiskopf et al., 2020). Both virus-specific CD4 and CD8 T cells were detected in all patients at average frequencies of 1.4% and 1.3%, respectively, and very limited phenotyping according to CD45RA and CCR7 expression status characterized these cells predominantly as either CD4 Tcm (central memory) or CD8 Tem (effector memory) and Temra (effector memory RA) cells. This study is notable for the use of large complementary peptide pools comprising 1,095 SARS-Cov-2 epitopes (overlapping 15-mers for S protein as well as computationally predicted HLA-I- and -II-restricted epitopes for all other viral proteins) as antigen-specific stimuli that revealed a preferential specificity of both CD4 and CD8 T cells for S protein epitopes, with the former population modestly increasing over ∼10–30 days after initial onset of symptoms. A caveat, however, pertains to the identification of specific T cells by induced CD69 and CD137 co-expression, since upregulation of CD137 by CD4 T cells, in contrast to CD154, may preferentially capture regulatory T cells (Treg) (Bacher et al., 2016). Further analyses of S protein-specific T cells by ELISA demonstrated robust induction of IFN-γ, TNF-α, and IL-2 concomitant with lower levels of IL-5, IL-13, IL-9, IL-10, and IL-22. A third report focused on S-specific CD4 T cell responses in 18 patients with mild, severe, or critical COVID-19 using overlapping peptide pools and induced CD154 and CD137 co-expression as a readout for antiviral CD4 T cells. Such cells were present in 83% of cases and presented with enhanced CD38, HLA-DR, and Ki-67 expression indicative of recent in vivo activation (Braun et al., 2020). Of note, the authors also detected low frequencies of S-reactive CD4 T cells in 34% of SARS-CoV-2 seronegative healthy control donors. However, these CD4 T cells lacked phenotypic markers of activation and were specific for C-terminal S protein epitopes that are highly similar to endemic human CoVs, suggesting that crossreactive CD4 memory T cells in some populations (e.g., children and younger patients that experience a higher incidence of hCoV infections) may be recruited into an amplified primary SARS-CoV-2-specific response (Braun et al., 2020). Similarly, endemic CoV-specific CD4 T cells were previously shown to recognize SARS-CoV1 determinants (Gioia et al., 2005). How previous infections with endemic CoV may affect immune responses to SARS-CoV-2 will need to be further investigated.
Finally, in general accordance with the above findings on the induction of SARS-CoV-2-specific T cells, using TCR sequencing (TCR-seq), Huang et al. and Liao et al. reported greater TCR clonality of peripheral blood (Huang et al., 2020c) as well as BAL T cells (Liao et al., 2020) in patients with mild versus severe COVID-19. Moving forward, a comprehensive identification of immunogenic SARS-CoV-2 epitopes recognized by T cells (Campbell et al., 2020), as well as further studies on convalescent patients who recovered from mild and severe disease, will be particularly important.