SARS-CoV-2 non-seroconvertors present t-cell responses with decreased activation

ABSTRACT

Background: Many immune studies of SARS-CoV-2 (CoV-2) infection have focused on the generation of virus-specific as a means of protection. However, a small group of CoV-2 infected individuals called Non-seroconverters (NSC), do not generate antibodies but experience a mild or moderate disease course. Identifying mechanism of CoV-2 control in NSC may inform the development of novel therapeutics and vaccines approaches. Methods: We identified eleven CoV-2 NSC (3.6%) from the King-cohort study (PI-20-217). NSC were defined by a positive CoV-2 PCR at the time of diagnosis in the absence of IgG, IgA and IgM in serum and plasma measured by two independent ELISA techniques. For comparison, we identify groups of CoV-2 convalescent (n=15) and low-neutralizers (n=15). We measured T-cell responses to the CoV-2 Spike (S) and Nucleocapsid (NP) recombinant proteins in PBMCs by ELISPOT and flow cytometry. We combined T-cell surface and lineage markers together with PD-1, functional (TNF, IFN-y, and IL-2) and activation induced markers (AIM: CD25, CD137 and OX40). Results: We identified CoV-2 specific CD4+ and CD8+ T-cells against the S and the NP in NSC individuals. All NSC responded to S by production of one or more cytokine in either CD4+ or CD8+ T-cells, and 57% responded to NP. Specific-CD8+ T cells against S in NSC were characterized by IFN-y, and TNF production, and we observed higher levels of TNF production as compared to low neutralizers (p=0.02). No differences were found in IFN-y, IL-2 and TNF production in S-specific CD4+ T cells between groups, nor in NP CD8+ or CD4+ T-cell responses. The levels of CD137/OX40 in CD8+ and CD4+ T cells were significantly lower in NSC in response to S (p=0.006, and p=0.012). Also, lower levels of PD-1 were observed in CD8+ T cells in response to NP in NSC (p=0.017). Conclusion: We provide evidence of SARS-CoV2 cellular immunity in NSC individuals despite the absence of humoral neutralizing responses. CD8+ and CD4+ T cells against the S and NP were present in NSC and characterized by TNF production in CD8+ T-cells in responses to S when compared to low neutralizers. Decreased levels of activation markers were observed in NSCs following S and NP stimulation. We propose a protective role of cellular immunity in NSC potentially driven by preexisting cellular responses.