# Distinct HLA Haplotypes Are Associated With an Altered Strength of SARS‐CoV‐2‐Specific T‐Cell Responses and Unfavorable Disease Courses

## TL;DR

This study finds that certain HLA haplotypes are linked to weaker T-cell responses and worse outcomes in COVID-19, likely due to T-cell issues rather than fewer virus epitopes.

## Contribution

The study identifies T-cell intrinsic factors, not epitope presentation, as key to disease severity and predicts stable T-cell immunity against future SARS-CoV-2 variants.

## Key findings

- HLA haplotypes linked to severe disease do not show reduced epitope presentation potential.
- T-cell intrinsic factors likely influence disease severity rather than epitope availability.
- T-cell epitopes are not from highly mutated regions, suggesting stable T-cell immunity against new variants.

## Abstract

Infection with SARS‐CoV‐2 results in mild to severe COVID‐19 disease courses. Several studies showed the association of impaired T‐cell responses and certain HLA haplotypes with disease severity. However, it remained unclear if T‐cell activation was compromised due to a general reduction of presented epitopes or other intrinsic factors within APCs or T cells. Furthermore, a potential reduction of presented epitopes would suggest if an upcoming SARS‐CoV‐2 variant could escape T‐cell immunity. Hence, knowledge about the T‐cell epitope landscape of SARS‐CoV‐2 would allow to better understand mechanisms leading to severe disease and to estimate the potential stability of the T‐cell response in light of virus evolution, which might provide insights for future vaccine designs. Hence, in the present study, the T‐cell epitope landscape of SARS‐CoV‐2 was determined via in vitro T‐cell stimulation plus in silico prediction. HLAs associated with mild and severe disease courses showed almost the same potential in epitope presentation, suggesting intrinsic factors of APCs or T cells as contributors to the more severe disease courses. As T‐cell epitopes did also not originate from regions of SARS‐CoV‐2 having shown high mutation rates in the past, a relatively stable T‐cell response can be expected regarding new SARS‐CoV‐2 strains in the future. Analysis of the T‐cell epitope landscape of SARS‐CoV‐2 suggests T‐cell intrinsic factors as likely modulators of disease severity and that the capacity of MHC‐peptide presentation remains stable among circulating SARS‐CoV‐2 viral strains.

Analysis of the T‐cell epitope landscape of SARS‐CoV‐2 suggests T‐cell intrinsic factors as likely modulators of disease severity and that the capacity of MHC‐peptide presentation remains stable among circulating SARS‐CoV‐2 viral strains.