Despite the growing knowledge of T cell responses in COVID-19 patients, there is a lack of detailed characterizations for T cell-antigen interactions and T cell functions. Here, with a predicted peptide library from SARS-CoV-2 S and N proteins, we found that specific CD8⁺ T cell responses were identified in over 75% of COVID-19 convalescent patients (15/20) and an epitope from the N protein, N^361-369 (KTFPPTEPK), was the most dominant epitope from our selected peptide library. Importantly, we discovered 2 N^361-369-specific T cell receptors (TCRs) with high functional avidity that were independent of the CD8 co-receptor. These TCRs exhibited complementary cross-reactivity to several presently reported N^361-369 mutant variants, as to the wild-type epitope. Further, the natural functions of these TCRs in the cytotoxic immunity against SARS-CoV-2 were determined with dendritic cells (DCs) and the lung organoid model. We found that the N^361-369 epitope could be normally processed and endogenously presented by these different types of antigen presenting cells, to elicit successful activation and effective cytotoxicity of CD8⁺ T cells ex vivo. Our study evidenced potential mechanisms of cellular immunity to SARS-CoV-2, and illuminated potential ways of viral clearance in COVID-19 patients. These results indicate that utilizing CD8-independent TCRs against SARS-CoV-2-associated antigens may provide functional superiority that is beneficial for the adoptive cell immunotherapies based on natural or genetically engineered T cells. Additionally, this information is highly relevant for the development of the next-generation vaccines with protections against continuously emerged SARS-CoV-2 mutant strains.

The pandemic of COVID-19 caused by SARS-CoV-2 has made serious threats to the public health. Antibodies have been considered as promising therapeutics for the prevention and treatment of pathogens. So far, effectors that can influence the sustainability of SARS-CoV-2 specific antibodies in COVID-19 patients are still unclear. In this paper, we attempted to find potential key factors correlated with SARS-CoV-2 specific antibodies. Transcriptional analysis with the peripheral blood mononuclear cells (PBMCs) revealed proportional changes of immune cell subsets in COVID-19 convalescent patients, including a substantial decrease of monocytes and evident increase of dendritic cells (DCs). Moreover, we found that the gene expressions of chemokines associated with monocyte/macrophage were significantly up-regulated during the COVID-19 recovery phase. Most importantly, we found a set of 27 immune genes corresponding to a comparatively lower amount of SARS-CoV-2 specific antibodies, and identified two hub genes, IL1β and IL6, the protein expressions of which exhibited negative correlation with the immunoglobulin G (IgG) levels in COVID-19 convalescent sera. In addition, we found that high expressions of these 2 hub genes during the convalescent stage were negatively associated with the plasma cell marker CD138. Our study presented two key inflammatory factors correlated to the low level of SARS-CoV-2 specific antibodies, which indicated the potential regulatory process of plasmatic antibodies levels in some COVID-19 convalescent patients.

The important role of lncRNAs and miRNAs in directing immune responses has become increasingly clear. Recent evidence conforms that miRNAs and lncRNAs are involved in NK cell biology and diseases through RNA–protein, RNA–RNA, or RNA–DNA interactions. In this view, we summarize the contribution of miRNAs and lncRNAs to NK cell lineage development, activation and function, highlight the biological significance of functional miRNAs or lncRNAs in NKTL and discuss the potential of these miRNAs and lncRNAs as innovative biomarkers/targets for NKTL early diagnosis, target treatment and prognostic evaluations.