AUTHOR=Schreibing Felix , Hannani Monica T. , Kim Hyojin , Nagai James S. , Ticconi Fabio , Fewings Eleanor , Bleckwehl Tore , Begemann Matthias , Torow Natalia , Kuppe Christoph , Kurth Ingo , Kranz Jennifer , Frank Dario , Anslinger Teresa M. , Ziegler Patrick , Kraus Thomas , Enczmann Jürgen , Balz Vera , Windhofer Frank , Balfanz Paul , Kurts Christian , Marx Gernot , Marx Nikolaus , Dreher Michael , Schneider Rebekka K. , Saez-Rodriguez Julio , Costa Ivan , Hayat Sikander , Kramann Rafael TITLE=Dissecting CD8+ T cell pathology of severe SARS-CoV-2 infection by single-cell immunoprofiling JOURNAL=Frontiers in Immunology VOLUME=13 YEAR=2022 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.1066176 DOI=10.3389/fimmu.2022.1066176 ISSN=1664-3224 ABSTRACT=Introduction

SARS-CoV-2 infection results in varying disease severity, ranging from asymptomatic infection to severe illness. A detailed understanding of the immune response to SARS-CoV-2 is critical to unravel the causative factors underlying differences in disease severity and to develop optimal vaccines against new SARS-CoV-2 variants.

Methods

We combined single-cell RNA and T cell receptor sequencing with CITE-seq antibodies to characterize the CD8+ T cell response to SARS-CoV-2 infection at high resolution and compared responses between mild and severe COVID-19.

Results

We observed increased CD8+ T cell exhaustion in severe SARS-CoV-2 infection and identified a population of NK-like, terminally differentiated CD8+ effector T cells characterized by expression of FCGR3A (encoding CD16). Further characterization of NK-like CD8+ T cells revealed heterogeneity among CD16+ NK-like CD8+ T cells and profound differences in cytotoxicity, exhaustion, and NK-like differentiation between mild and severe disease conditions.

Discussion

We propose a model in which differences in the surrounding inflammatory milieu lead to crucial differences in NK-like differentiation of CD8+ effector T cells, ultimately resulting in the appearance of NK-like CD8+ T cell populations of different functionality and pathogenicity. Our in-depth characterization of the CD8+ T cell-mediated response to SARS-CoV-2 infection provides a basis for further investigation of the importance of NK-like CD8+ T cells in COVID-19 severity.