Protective and Pathogenic T Cell Immunity During SARS-CoV-2 Infection

The current pandemic coronavirus disease 2019 (COVID-19) with the newly emerged severe acute respiratory syndrome (SARS) coronavirus SARS-CoV-2 causes grave challenges to the medical and economic systems and to people world-wide. Besides massive measures to contain the pandemic, intense efforts are ongoing to identify drugs that could be used as antivirals and also vaccines that may protect the many individuals that have not yet been infected, particularly those at high risk of suffering severe clinical courses. Towards vaccine development and to understand factors related to organ/tissue involvement, it is paramount to analyze adaptive immune responses against the virus with respect to protection but also regarding cross-recognition of self-/autoantigens from different tissues and the involvement in organ pathologies. CD4+ T cells are critical for helping efficient cytotoxic CD8+ T cell responses and also neutralizing antibody production. They are also the main mediators of autoimmune reactions. Here, we propose to use a unique and completely unbiased epitope discovery approach for the identification of immunodominant target antigens (viral and self-antigens) for SARS-CoV-2-specific CD4+ and CD8+ T cells. Our methodology allows the identification of the specific target epitopes and to assess, which T cell responses are broadly SARS-CoV-2-reactive and likely protective against the prototype isolate, other SARS-CoV-2 isolates and putatively even other coronaviruses. Furthermore, it systematically identifies, which autoantigens are cross-recognized by SARS-CoV-2-specific CD4+ and CD8+ T cells. We will characterize SARS-CoV-2 CD4+ and CD8+ T cell clones after SARS-CoV-2 exposure and different disease courses with respect to immunodominant epitopes, cross-reactivity with autoantigens, phenotype, and function. New targets will be validated in larger cohorts post-infection. The antigen discovery approach will allow to address if immune responses are involved in clinical manifestations, for example prolonged course of infection due to inefficient immunity or, conversely, organ pathology such as pneumonia, pulmonary fibrosis, endotheliitis, or nervous system manifestations due to an overshooting/pathogenic immune response.