Low avidity CD4+ T cell responses to SARS-CoV-2 in unexposed individuals and humans with severe COVID-19

Bacher, Petra; Rosati, Elisa; Esser, Daniela; Martini, Gabriela Rios; Saggau, Carina; Schiminsky, Esther; Dargvainiene, Justina; Schöder, Ina; Wieters, Imke; Khodamoradi, Yascha; Eberhardt, Fabian; Vehreschild, Maria J.G.T.; Neb, Holger; Sonntagbauer, Michael; Conrad, Claudio; Tran, Florian; Rosenstiel, Philip; Markewitz, Robert; Wandinger, Klaus-Peter; Augustin, Max; Rybniker, Jan; Kochanek, Matthias; Leypoldt, Frank; Cornely, Oliver A.; Koehler, Philipp; Franke, Andre; Scheffold, Alexander

CD4+ T cells reactive against SARS-CoV-2 can be found in unexposed individuals and these are suggested to arise in response to common cold corona viruses (CCCoVs) infection. Here, we utilized SARS-CoV-2-reactive CD4+ T cell enrichment to examine the antigen-avidity and clonality of these cells, as well as the relative contribution of CCCoV cross-reactivity. SARS-CoV-2-reactive CD4+ memory T-cells were present in virtually all unexposed individuals examined, displaying low functional avidity and multiple, highly variable cross-reactivities that were not restricted to CCCoVs. SARS-CoV-2 reactive CD4+ T cells from COVID-19 patients lacked cross-reactivity to CCCoVs, irrespective of strong memory T-cell responses against CCCoV in all donors analysed. In severe but not mild COVID-19, SARS-CoV-2-specific T-cells displayed low functional avidity and clonality, despite increased frequencies. Our findings identify low avidity CD4+T cell responses as a hallmark of severe COVID-19, and argue against a protective role for CCCoV reactive T cells in SARS-CoV-2 infection.