Understanding the hallmarks of the immune response to SARS-CoV-2 is critical for fighting the COVID-19 pandemic. We assessed antibody and T cell reactivity in convalescent COVID-19 patients and healthy donors sampled both prior to and during the pandemic. Healthy donors examined during the pandemic exhibited increased numbers of SARS-CoV-2-specific T cells, but no humoral response. Their probable exposure to the virus resulted in either asymptomatic infection without antibody secretion, or activation of pre-existing immunity. In convalescent patients, we observed a public and diverse T cell response to SARS-CoV-2 epitopes, revealing T cell receptor (TCR) motifs with germline-encoded features. Bulk CD4 + and CD 8+ T cell responses to the spike glycoprotein were mediated by groups of homologous TCRs, some of them shared across multiple donors. Overall, our results demonstrate that the T cell response to SARS-CoV-2, including the identified set of TCRs, can serve as a useful biomarker for surveying antiviral immunity.

COVID-19 is a global pandemic caused by the SARS-CoV-2 coronavirus. T cells play a key role in the adaptive antiviral immune response by killing infected cells and facilitating the selection of virus-specific antibodies. However, neither the dynamics and cross-reactivity of the SARS-CoV-2-specific T-cell response nor the diversity of resulting immune memory is well understood. In this study, we use longitudinal high-throughput T-cell receptor (TCR) sequencing to track changes in the T-cell repertoire following two mild cases of COVID-19. In both donors, we identified CD4+ and CD8+ T-cell clones with transient clonal expansion after infection. We describe characteristic motifs in TCR sequences of COVID-19-reactive clones and show preferential occurrence of these motifs in publicly available large dataset of repertoires from COVID-19 patients. We show that in both donors, the majority of infection-reactive clonotypes acquire memory phenotypes. Certain T-cell clones were detected in the memory fraction at the pre-infection time point, suggesting participation of pre-existing cross-reactive memory T cells in the immune response to SARS-CoV-2.

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Objectives To predict the spread of coronavirus disease (COVID‐19), information regarding the immunological memory for disease‐specific antigens is necessary. The possibility of reinfection, as well as the efficacy of vaccines for COVID‐19 that are currently under development, will largely depend on the quality and longevity of immunological memory in patients. To elucidate the process of humoral immunity development, we analysed the generation of plasmablasts and virus receptor‐binding domain (RBD)‐specific memory B (Bmem) cells in patients during the acute phase of COVID‐19. Methods The frequencies of RBD‐binding plasmablasts and RBD‐specific antibody‐secreting cells (ASCs) in the peripheral blood samples collected from patients with COVID‐19 were measured using flow cytometry and the ELISpot assay. Results The acute phase of COVID‐19 was characterised by the transient appearance of total as well as RBD‐binding plasmablasts. ELISpot analysis indicated that most patients exhibited a spontaneous secretion of RBD‐specific ASCs in the circulation with good correlation between the IgG and IgM subsets. IL‐21/CD40L stimulation of purified B cells induced the activation and proliferation of Bmem cells, which led to the generation of plasmablast phenotypic cells as well as RBD‐specific ASCs. No correlation was observed between the frequency of Bmem cell‐derived and spontaneous ASCs, suggesting that the two types of ASCs were weakly associated with each other. Conclusion Our findings reveal that SARS‐CoV‐2‐specific Bmem cells are generated during the acute phase of COVID‐19. These findings can serve as a basis for further studies on the longevity of SARS‐CoV‐2‐specific B‐cell memory.

Overexpression of TNF contributes to pathogenesis of multiple autoimmune diseases, accounting for a remarkable success of anti-TNF therapy. TNF is produced by a variety of cell types, and it can play either a beneficial or a deleterious role. In particular, in autoimmunity pathogenic TNF may be derived from restricted cellular sources. In this study we evaluated the feasibility of cell-type-restricted TNF inhibition in vivo. To this end, we engineered MYSTI (Myeloid-Specific TNF Inhibitor)-a recombinant bispecific antibody that binds to the F4/80 surface molecule on myeloid cells and to human TNF (hTNF). In macrophage cultures derived from TNF humanized mice MYSTI could capture the secreted hTNF, limiting its bioavailability. Additionally, as evaluated in TNF humanized mice, MYSTI was superior to an otherwise analogous systemic TNF inhibitor in protecting mice from lethal LPS/D-Galactosamine-induced hepatotoxicity. Our results suggest a novel and more specific approach to inhibiting TNF in pathologies primarily driven by macrophage-derived TNF.anti-cytokine therapy | TNF | bispecific antibody | autoimmunity | humanized mice