Low avidity circulating SARS-CoV-2 reactive CD8+ T cells with proinflammatory TEMRA phenotype are associated with post-acute sequelae of COVID-19

Krystallenia Paniskaki; Margarethe J Konik; Moritz Anft; Harald Heidecke; Toni L Meister; Stephanie Pfaender; Adalbert Krawczyk; Markus Zettler; Jasmin Jäger; Anja Gaeckler; Sebastian Dolff; Timm H Westhoff; Hana Rohn; Ulrik Stervbo; Carmen Scheibenbogen; Oliver Witzke; Nina Babel

doi:10.3389/fmicb.2023.1196721

Low avidity circulating SARS-CoV-2 reactive CD8+ T cells with proinflammatory TEMRA phenotype are associated with post-acute sequelae of COVID-19

Front Microbiol. 2023 Jun 2:14:1196721. doi: 10.3389/fmicb.2023.1196721. eCollection 2023.

Authors

Krystallenia Paniskaki^{1

2}, Margarethe J Konik¹, Moritz Anft², Harald Heidecke³, Toni L Meister⁴, Stephanie Pfaender⁴, Adalbert Krawczyk¹, Markus Zettler¹, Jasmin Jäger^{1

2}, Anja Gaeckler⁵, Sebastian Dolff¹, Timm H Westhoff⁶, Hana Rohn¹, Ulrik Stervbo², Carmen Scheibenbogen⁷, Oliver Witzke¹, Nina Babel^{2

8}

Affiliations

¹ Department of Infectious Diseases, West German Centre of Infectious Diseases, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
² Center for Translational Medicine and Immune Diagnostics Laboratory, Medical Department I, Marien Hospital Herne, University Hospital of the Ruhr-University Bochum, Bochum, Germany.
³ CellTrend GmbH, Luckenwalde, Germany.
⁴ Department of Molecular and Medical Virology, Ruhr-University Bochum, Bochum, Germany.
⁵ Department of Nephrology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
⁶ Medical Department I, Marien Hospital Herne, University Hospital of the Ruhr-University Bochum, Herne, Germany.
⁷ Institute for Medical Immunology, Charité-Universitätsmedizin Berlin, Campus Virchow, Berlin, Germany.
⁸ Berlin Institute of Health at Charité - University Clinic Berlin, BIH Center for Regenerative Therapies (BCRT) Berlin, Berlin, Germany.

Abstract

The role of adaptive SARS-CoV-2 specific immunity in post-acute sequelae of COVID-19 (PASC) is not well explored, although a growing population of convalescent COVID-19 patients with manifestation of PASC is observed. We analyzed the SARS-CoV-2-specific immune response, via pseudovirus neutralizing assay and multiparametric flow cytometry in 40 post-acute sequelae of COVID-19 patients with non-specific PASC manifestation and 15 COVID-19 convalescent healthy donors. Although frequencies of SARS-CoV-2-reactive CD4+ T cells were similar between the studied cohorts, a stronger SARS-CoV-2 reactive CD8+ T cell response, characterized by IFNγ production and predominant T_EMRA phenotype but low functional TCR avidity was detected in PASC patients compared to controls. Of interest, high avidity SARS-CoV-2-reactive CD4+ and CD8+ T cells were comparable between the groups demonstrating sufficient cellular antiviral response in PASC. In line with the cellular immunity, neutralizing capacity in PASC patients was not inferior compared to controls. In conclusion, our data suggest that PASC may be driven by an inflammatory response triggered by an expanded population of low avidity SARS-CoV-2 reactive pro-inflammatory CD8+ T cells. These pro-inflammatory T cells with TEMRA phenotype are known to be activated by a low or even without TCR stimulation and lead to a tissue damage. Further studies including animal models are required for a better understanding of underlying immunopathogensis. Summary: A CD8+ driven persistent inflammatory response triggered by SARS-CoV-2 may be responsible for the observed sequelae in PASC patients.

Keywords: BMI; PASC; T cells; long COVID; post-acute sequelae of COVID-19.