The polarity and specificity of SARS-CoV2 -specific T lymphocyte responses determine disease susceptibility

FAHRNER, J.-E.; CARRIER, A.; Lyon COVID study group,; DE SOUSA, E.; DRUBAY, D.; DUBUISSON, A.; GERAUD, A.; GOUBET, A.-G.; FERRERE, G.; HADDAD, Y.; LAHMAR, I.; MAZZENGA, M.; MELENOTTE, C.; PICARD, M.; THELEMAQUE, C.; CERBONE, L.; LERIAS, J. R.; LAPARRA, A.; BERNARD, A.; KLOECKNER, B.; GAZZANO, M.; DANLOS, F.-X.; TERRISSE, S.; ALVES COSTA SILVA, C.; PIZZATO, E.; FLAMENT, C.; LY, P.; TARTOUR, E.; MEZIANI, L.; AHMED-BELKACEM, A.; MIYARA, M.; Gorochov, G.; BARLESI, F.; PRADON, C.; GALLOIS, E.; POMMERET, F.; COLOMBA, E.; LAVAUD, P.; DEUTSCH, E.; GACHOT, B.; SPANO, J.-P.; Merad, M.; SCOTTE, F.; MAR,

Optimal vaccination and immunotherapy against coronavirus disease COVID-19 relies on the in-depth comprehension of immune responses determining the individual susceptibility to be infected by SARS-CoV-2 and to develop severe disease. We characterized the polarity and specificity of circulating SARS-CoV-2-specific T cell responses against whole virus lysates or 186 unique peptides derived from the SARS-CoV-2 or SARS-CoV-1 ORFeome on 296 cancer-bearing and 86 cancer-free individuals who were either from the pre-COVID-19 era (67 individuals) or contemporary COVID-19-free (237 individuals) or who developed COVID-19 (78 individuals) in 2020/21. The ratio between the prototypic T helper 1 (TH1) cytokine, interleukin-2, and the prototypic T helper 2 (TH2) cytokine, interleukin-5 (IL-5), released from SARS-CoV-2-specific memory T cells measured in early 2020, among SARS-CoV-2-negative persons, was associated with the susceptibility of these individuals to develop PCR-detectable SARS-CoV-2 infection in late 2020 or 2021. Of note, T cells from individuals who recovered after SARS-CoV-2 re-infection spontaneously produced elevated levels of IL-5 and secreted the immunosuppressive TH2 cytokine interleukin-10 in response to SARS-CoV-2 lysate, suggesting that TH2 responses to SARS-CoV-2 are inadequate. Moreover, individuals susceptible to SARS-CoV-2 infection exhibited a deficit in the TH1 peptide repertoire affecting the highly mutated receptor binding domain (RBD) amino acids (331-525) of the spike protein. Finally, current vaccines successfully triggered anti-RBD specific TH1 responses in 88% healthy subjects that were negative prior to immunization. These findings indicate that COVID-19 protection relies on TH1 cell immunity against SARS-CoV-2 S1-RBD which in turn likely drives the phylogenetic escape of the virus. The next generation of COVID-19 vaccines should elicit high-avidity TH1 (rather than TH2)-like T cell responses against the RBD domain of current and emerging viral variants.