T cells target Covid-19 virus.

 Here we describe an assay that allows direct detection and characterization of SARS-CoV-2 spike glycoprotein (S)-reactive CD4+ T cells in peripheral blood. We demonstrate the presence of S-reactive CD4+ T cells in 83% of COVID-19 patients, as well as in 34% of SARS-CoV-2 seronegative healthy donors, albeit at lower frequencies. Strikingly, in COVID-19 patients S-reactive CD4+ T cells equally targeted both N-terminal and C-terminal parts of S whereas in healthy donors S-reactive CD4+ T cells reacted almost exclusively to the Cterminal part that is a) characterized by higher homology to spike glycoprotein of human endemic "common cold" coronaviruses, and b) contains the S2 subunit of S with the cytoplasmic peptide (CP), the fusion peptide (FP), and the transmembrane domain (TM) but not the receptor-binding domain (RBD). S-reactive CD4+ T cells from COVID-19 patients were further distinct to those from healthy donors as they co-expressed higher levels of CD38 and HLA-DR, indicating their recent in vivo activation. Our study is the first to directly measure SARS-CoV-2-reactive T cell responses providing critical tools for large scale testing, in depth epitope mapping and characterization of potential cross-reactive cellular immunity to SARS-CoV-2. The presence of pre-existing SARS-CoV-2-reactive T cells in healthy donors is of high interest but larger scale prospective cohort studies are needed to assess whether their presence is a correlate of protection or pathology. Results of such studies will be key for a mechanistic understanding of the SARS-CoV-2 pandemic, adaptation of containment methods and to support vaccine development.

Competing Interest Statement

The authors Jürgen Schmitz, Stefan Miltenyi, Florian Kern, Ulf Reimer, Holger Wenschuh are employed at non-academic cooperations.

Funding Statement

We thank Ulf Klein (Leeds, UK) und Hans-Peter Herzel (Berlin) for critical discussion. This work was supported by the German Research Foundation (KFO339 to J.B and F.F., SFB-TR84 projects A4, B6 to S.H., B8 to M.M., C6 to M.W., C8, C10 to L.E.S., C9 to M.W, N.S., and by the German Federal Ministry of Education and Research (BMBF-RAPID to S.H., C.D., and CAPSyS to M.W., N.S.).

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