SARS-CoV-2-derived peptides define heterologous and COVID-19-induced T cell recognition

Abstract

T cell immunity is central for the control of viral infections. To characterize T cell immunity, but also for the development of vaccines, identification of exact viral T cell epitopes is fundamental. Here we identify and characterize multiple dominant and subdominant SARS-CoV-2 HLA class I and HLA-DR peptides as potential T cell epitopes in COVID-19 convalescent and unexposed individuals. SARS-CoV-2-specific peptides enabled detection of post-infectious T cell immunity, even in seronegative convalescent individuals. Cross-reactive SARS-CoV-2 peptides revealed pre-existing T cell responses in 81% of unexposed individuals and validated similarity with common cold coronaviruses, providing a functional basis for heterologous immunity in SARS-CoV-2 infection. Diversity of SARS-CoV-2 T cell responses was associated with mild symptoms of COVID-19, providing evidence that immunity requires recognition of multiple epitopes. Together, the proposed SARS-CoV-2 T cell epitopes enable identification of heterologous and post-infectious T cell immunity and facilitate development of diagnostic, preventive and therapeutic measures for COVID-19. NATURE IMMUNOLOGY | www.nature.com/natureimmunology Articles NATuRE ImmuNOLOgy evidence that antibody responses are short-lived and can even cause or aggravate virus-associated lung pathology 16,17. With regard to SARS-CoV-2, very recent studies 18-20 described CD4 + and CD8 + T cell responses to viral peptide megapools in donors that had recovered from COVID-19 and individuals not exposed to SARS-CoV-2, the latter being indicative of potential T cell cross-reactivity 21,22. The exact viral epitopes that mediate these T cell responses against SARS-CoV-2, however, were not identified and characterized in detail in these studies, but are prerequisite (1) to delineate the role of post-infectious and heterologous T cell immunity in COVID-19, (2) for establishing diagnostic tools to identify SARS-CoV-2 immunity and, most importantly, (3) to define target structures for the development of SARS-CoV-2-specific vaccines and immunotherapies. In this study, we define SARS-CoV-2-specific and cross-reactive CD4 + and CD8 + T cell epitopes in a large collection of SARS-CoV-2 convalescent as well as nonexposed individuals and their relevance for immunity and the course of COVID-19 disease. Results Identification of SARS-CoV-2-derived peptides. A new prediction and selection workflow, based on the integration of the algorithms SYFPEITHI and NetMHCpan, identified 1,739 and 1,591 auspicious SARS-CoV-2-derived HLA class I-and HLA-DR-binding peptides across all ten viral open-reading frames (ORFs) (Fig. 1a and Extended Data Fig. 1a,b). Predictions were performed for the ten and six most common HLA class I

Impact of pre-existing T cell immunity to SARS-CoV-2 in uninfected individuals with COVID-19 mortality in different countries

“…If this conclusion is correct, we may be approaching the crossing of the herd immunity threshold required to stop the COVID-19 pandemic in not very distant future. Collectively, present findings indicate that the heterologous immunity facilitated by cross-reactive T cells pre-existing in uninfected individuals may be one of important contributing factors affecting the clinical course of the COVID-19 pandemic(7,8) and strongly support the previously articulated rationale (3) for worldwide prospective studies precisely mapping the levels of pre-existing immune cross-reactivity against SARS-CoV-2 to the clinical course and outcomes of the pandemic.LimitationsOne of the most significant limitations of this work is the small sample size of all reported to date studies on the levels of pre-existing T cell immunity against the SARS-CoV-2 in different countries, which is difficult to justify as representative samples of corresponding populations.…”

“…However, the most recent study (7) confirmed and extended these findings based on the analyses of 185 uninfected individuals, thus addressing to a significant degree this limitation. In unexposed to the SARS-CoV-2 individuals, the cross-reactive T cells were detected against 9 of 29 (31%) of the validated HLA class I and to 14 of 20 (70%) HLA-DR T cell peptide epitopes (7). Recognition frequencies against individual T cell epitopes in unexposed individuals were highly variable reaching up to 27% and 44% for the best-performing HLA class I and HLA-DR peptide epitopes, respectively (7).…”

“…It has been pointed out that the common major limitation of these studies was the relatively small numbers of donors contributing blood samples for the analyses (6). However, the most recent study (7) confirmed and extended these findings based on the analyses of 185 uninfected individuals, thus addressing to a significant degree this limitation. In unexposed to the SARS-CoV-2 individuals, the cross-reactive T cells were detected against 9 of 29 (31%) of the validated HLA class I and to 14 of 20 (70%) HLA-DR T cell peptide epitopes (7).…”

Potential CD8+ T Cell Cross-Reactivity Against SARS-CoV-2 Conferred by Other Coronavirus Strains

“…In a separate study, Nelde et al (33) predicted 1,739 SARS-CoV-2 derived HLA-I peptides to be immunogenic based on integration of two algorithms, SYFPEITHI and NetMHCpan. They then selected 100 from 1,739 peptides to proceed for functional validation and reported 29/100 (29%) peptides as naturally occurring CD4+ or CD8+ T-cell epitopes.…”

The known unknowns of T cell immunity to COVID-19

“…Previous studies have demonstrated that SARS-CoV-and MERS-CoV-specific T cells can be detected many years after infection (21)(22)(23). Likewise, SARS-CoV-2-specific CD4 + and CD8 + T cells are distinguished in a vast majority of convalescent donors (7,9,21,(24)(25)(26)(27). Studies using peripheral blood have reported stronger SARS-CoV-2specific CD4 + than CD8 + T cell responses in most subjects.…”