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

Abstract

The SARS-CoV-2 pandemic calls for the rapid development of diagnostic, preventive, and therapeutic approaches. CD4+ and CD8+ T cell-mediated immunity is central for control of and protection from viral infections[1-3]. A prerequisite to characterize T-cell immunity, but also for the development of vaccines and immunotherapies, is the identification of the exact viral T-cell epitopes presented on human leukocyte antigens (HLA)[2-8]. This is the first work identifying and characterizing SARS-CoV-2-specific and cross-reactive HLA class I and HLA-DR T-cell epitopes in SARS-CoV-2 convalescents (n = 180) as well as unexposed individuals (n = 185) and confirming their relevance for immunity and COVID-19 disease course. SARS-CoV-2-specific T-cell epitopes enabled detection of post-infectious T-cell immunity, even in seronegative convalescents. Cross-reactive SARS-CoV-2 T-cell epitopes revealed preexisting T-cell responses in 81% of unexposed individuals, and validation of similarity to common cold human coronaviruses provided a functional basis for postulated heterologous immunity[9] in SARS-CoV-2 infection[10,11]. Intensity of T-cell responses and recognition rate of T-cell epitopes was significantly higher in the convalescent donors compared to unexposed individuals, suggesting that not only expansion, but also diversity spread of SARS-CoV-2 T-cell responses occur upon active infection. Whereas anti-SARS-CoV-2 antibody levels were associated with severity of symptoms in our SARS-CoV-2 donors, intensity of T-cell responses did not negatively affect COVID-19 severity. Rather, diversity of SARS-CoV-2 T-cell responses was increased in case of mild symptoms of COVID-19, providing evidence that development of immunity requires recognition of multiple SARS-CoV-2 epitopes. Together, the specific and cross-reactive SARS-CoV-2 T-cell epitopes identified in this work enable the identification of heterologous and post-infectious T-cell immunity and facilitate the development of diagnostic, preventive, and therapeutic measures for COVID-19.

Integrin activation enables simultaneous and sensitive detection of functional virus-specific CD4+ and CD8+ T cells

“…In line with other recent reports, we also observed in one unexposed donor very low frequencies of CD4 + and CD8 + T cells against spike and nucleocapsid proteins, respectively, probably due to cross-reactive cells primed against other SARS viruses [12][13][14]. We also used m24 Ab staining to con rm the induction of anti-vaccine CD4 + T cells after experimental immunization of a healthy volunteer with synthetic peptides from the spike and nucleocapsid proteins [9].…”

Epitopes targeted by T cells in convalescent COVID-19 patients

“…Results compiled from 8 experimental studies of T cell responses in a total of 1,259 convalescent COVID-19 patients (Le Bert et al, 2020;Chour et al, 2020;Peng et al, 2020;Nelde et al, 2020;Poran et al, 2020;Shomuradova et al, 2020;Ferretti et al, 2020;Snyder et al, 2020) revealed 303 unique T cell epitopes. Of these, 71 are CD8 + (HLA class I restricted), 21 are CD4 + (HLA class II restricted), while 211 epitopes had no HLA allele information reported ( Figure 1A).…”

“…Data was compiled from 8 immunological studies (as of 7 August 2020) reporting SARS-CoV-2 T cell epitopes in convalescent COVID-19 patients. More specifically, epitope data was extracted from Figure 3 in (Chour et al, 2020), Table 1 in (Shomuradova et al, 2020), Extended Data Tables 2 and 3 in (Nelde et al, 2020), Figure 3 in (Poran et al, 2020), Table 1 in (Ferretti et al, 2020), Table 1 in (Le Bert et al, 2020), Tables 1 and 2 in (Peng et al, 2020), and data deposited by authors of (Snyder et al, 2020) in the Immune Epitope Database (IEDB).…”

“…There is growing evidence to suggest that vaccines designed to produce targeted T cell responses may be particularly important. Preliminary studies have reported an inverse relation between the intensity of T cell responses and disease severity (Snyder et al, 2020;Nelde et al, 2020;Zhang et al, 2020), while the opposite has been observed for antibody titers (Long, Liu, et al, 2020;Snyder et al, 2020). Further investigations on larger cohorts are required, however these initial results suggest a protective role of T cells against COVID-19.…”

An immunodominance hierarchy exists in CD8+T cell responses to HLA-A*02:01-restricted epitopes identified from the non-structural polyprotein 1a of SARS-CoV-2

“…It is most likely that these individuals were previously infected with one of the four human coronaviruses (HCoV-229E, -NL63, -OC43 and -HKU1) that cause seasonal common cold. Nelde et al demonstrated evidence that the amino acid sequences of several SARS-CoV-2 T cell epitopes recognized by unexposed individuals are similar to some amino acid sequences in the four seasonal common cold human coronaviruses withidentities ranging from 10% to 89% (not 100% identity)(44). However, anyone has not shown evidence that people with this cross-reactivity are less susceptible to COVID-19.…”