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

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 coronavirus (CCCoV) 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 analyzed. 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. This research was supported by the German Research Foundation (DFG) under Germany’s Excellence Strategy — EXC 2167-390884018 Precision Medicine in Chronic Inflammation to P.B., A.F., and A.S.; RU5042-miTarget to P.B. and A.F.; DFG 433038070 to P.B., A.F., and A.S.; DFG 4096610003 to E.R; by a COVID-19 research grant from the Land Schleswig-Holstein, DIO002/ CoVispecT to P.B. and A.S.; the BMBF Grant AnDiPath (Fkz 03ZZ0838B) to A.S.; F.L. and D.E. were supported by the E-Rare Joint Transnational research support (ERA-Net, LE3064/2-1); and M.A. was supported by the BMBF Grant COVIM “NaFoUniMedCovid19” (FKZ: 01KX2021). F.L. is supported by German Ministry of Education and Research (01GM1908A). O.A.C. is supported by the German Federal Ministry of Research and Education and is funded by the DFG under Germany’s Excellence Strategy, CECAD, EXC 2030 – 390661388.