Identification and characterization of an immunodominant SARS-CoV-2-specific CD8 T cell response

Abstract

Global efforts are ongoing to develop vaccines against SARS-CoV-2 causing COVID-19. While there is accumulating information on antibody responses against SARS-CoV-2, less is known about CD8 T-cell recognized SARS-CoV-2 epitopes and the functional state of SARS- CoV-2-specific CD8 T cells. To address these issues, we analyzed samples from 18 COVID- 19 patients for CD8 T-cell recognition of 500 peptide HLA class I complexes, restricted by 10 common HLA alleles. Several epitopes derived from ORF1ab were identified, including an immunodominant epitope restricted by HLA-A*01:01. The immunodominance was further supported by high TCR diversity within the CD8 T cells specific for this epitope. Noteworthy, the ORF1ab is not included in the majority of vaccine candidates in development, which may influence their clinical activity. In-depth characterization of identified SARS-CoV-2-specific CD8 T cell responses revealed a lack of cytokine production and a gene expression profile inhibiting T cell re-activation and migration while sustaining cell survival.

SARS-CoV-2 human T cell epitopes: Adaptive immune response against COVID-19

“…Several Shomuradova et al, 2020;Ferretti et al, 2020;Gangaev et al, 2020;Habel et al, 2020;Sahin et al, 2020;Schulien et al, 2021;Saini et al, 2020Saini et al, , 2021 performed high-resolution analysis of SARS-CoV-2-specific CD8 + T cells using HLA multimers. However, none of the studies reported similar multimer analyses for CD4 + T cells, despite the fact that, in general, HLA class II restricted SARS-CoV-2-specific T cell responses are more pronounced than HLA class I restricted T cell responses (Grifoni et al, 2020;Nelde et al, 2021).…”

“…Two additional HLA-A*01:01 epitopes that overlap with TTDPSFLGRY (nsp3 818-828, sequence HTTDPSFLGRY, and nsp3 819-829, sequence TTDPSFLGRYM) were also identified as particularly dominant. The study by Gangaev et al screened 50 epitopes for 10 alleles using tetramers (500 total) in 18 donors and identified nine epitopes in total, including the immunodominant nsp3 epitope restricted by HLA-A*01:01 (Gangaev et al, 2020).…”

“…Rha et al reported that the S 269-277 epitope was specific to SARS-CoV-2, whereas the S 1220-1228 epitope was conserved in SARS-CoV-1 (Rha et al, 2021). In the study of Gangaev, of the 9 CD8 T cell epitopes they identified, 5 were unique for SARS-CoV-2 and 4 were shared between SARS-CoV-2 and SARS-CoV-1 (Gangaev et al, 2020). Prakash et al also studied conserved pan-species epitope sequences for all coronaviruses, including those responsible for zoonotic infections (Prakash et al, 2020).…”

“…Here, we focus on a specific topic: our current knowledge concerning the definition and recognition of SARS-CoV-2-derived T cell epitopes in humans. While the data related to this topic was initially sparse, 25 different studies have now been published as of March 15, 2021 (Chen et al, 2021;Ferretti et al, 2020;Gangaev et al, 2020;Habel et al, 2020;Joag et al, 2021;Kared et al, 2021;Keller et al, 2020;Le Bert et al, 2021Lee et al, 2020;Mahajan et al, 2020;Mateus et al, 2020;Nelde et al, 2021;Nielsen et al, 2020;Peng et al, 2020;Poran et al, 2020bPoran et al, , 2020aPrakash et al, 2020;Rha et al, 2021;Sahin et al, 2020;Saini et al, 2020, 2021, Schulien et al, 2021Sekine et al, 2020;Shomuradova et al, 2020;Snyder et al, 2020;Tarke et al, 2021a), which collectively report data from 1,197 human subjects (870 COVID-19 and 327 unexposed controls), leading to the identification of over 1,400 different CD4 (n = 382) and CD8 (n = 1052) T cell epitopes. These studies are listed in Table 1, which also captures whether these studies defined class I/CD8 epitopes and/or class II/CD4 epitopes.…”

Severely ill patients with COVID-19 display impaired exhaustion features in SARS-CoV-2–reactive CD8 + T cells

“…Recently, studies have begun to improve our knowledge about CD8 + T cells against SARS-CoV-2 (5)(6)(7)(8)(9)(10)(11)(12)(13)(14), but the molecular features that associate with poor clinical outcomes or differentiate them from other virus-reactive CD8 + T cells remain incompletely understood. Furthermore, despite the recent progress in understanding the biology of SARS-CoV-2-reactive and cross-reactive CD8 + T cells (5,8,9,12,(14)(15)(16)(17)(18)(19)(20)(21)(22)(23), comprehensive unbiased global profiling of SARS-CoV-2reactive and cross-reactive CD8 + T cells has not been performed to date. Here, we report on data generated by single-cell RNA sequencing of virus-reactive CD8 + T cells from COVID-19 patients with different clinical severity.…”