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Proliferative Receptor Binding Domain (RBD)-specific CD4+ T cells correlate with neutralizing antibody levels after natural SARS-CoV-2 infection and are induced following vaccination

ABSTRACT: Long-term immunity to SARS-CoV-2 infection, comprising neutralizing antibodies and T cell-mediated immunity, in a very large majority of the population, is required to reduce the current pandemic. We have investigated in detail the association between memory CD4 and CD8 T cells in recovered COVID-19 subjects, and their levels of neutralizing antibodies.The results show that RBD-specific memory CD4 T cells were particularly variable, and up to half of recovered individuals lacked these CD4 T cells and had much lower neutralizing antibody titres. Conversely, study of additional subjects identified as having low neutralizing antibody titres had very low levels of RBD-specific CD4 T cells. Furthermore, at both the protein and transcriptomic levels, these low antibody subjects had spike-specific CD4 T cells with a higher proportion of an inhibitory phenotype, including Foxp3 and CTLA-4, and less effector phenotype with T-bet and cytotoxic granzymes and perforin. Vaccination led to an improvement in RBD-specific memory CD4 T cells and neutralizing antibody titres in these at-risk subjects. Our results suggest that epitopes within the RBD-region should be the particular target of booster vaccines.

ORGANISM(S): synthetic construct Homo sapiens

PROVIDER: GSE198281 | GEO | 2024/01/24

REPOSITORIES: GEO

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Project description:Recently, several neutralizing anti-HIV antibodies have been isolated from memory B cells of HIV-infected individuals. However, despite extensive evidence of B-cell dysfunction in HIV disease, little is known about the cells from which these rare HIV-specific antibodies originate. Accordingly, HIV envelope gp140 and CD4 or co-receptor (CoR) binding site (bs) mutant probes were used to evaluate HIV-specific responses in the peripheral blood B cells of individuals at various stages of infection. In contrast to non-HIV responses, HIV-specific responses against gp140 were enriched within abnormal B cells, namely activated and exhausted memory subsets, which are largely absent in the blood of uninfected individuals. Responses against the CoRbs (a poorly-neutralizing epitope) arose early whereas those against the CD4bs (a well-characterized neutralizing epitope) were delayed and infrequent. Enrichment of the HIV-specific response within resting memory B cells, the predominant subset in uninfected individuals, did occur in certain infected individuals who maintained low levels of plasma viremia and immune activation with or without antiretroviral therapy. These findings were corroborated by transcriptional profiles. Taken together, our findings provide valuable insight into virus-specific B-cell responses in HIV infection and demonstrate that memory B-cell abnormalities may contribute to the ineffectiveness of the antibody response in infected individuals. HIV-specific responses against gp140 were enriched within abnormal B cells, namely activated (AM) and exhausted (tissue-like; TLM) memory subsets, which are largely absent in the blood of uninfected individuals. These responses are highest during the early stage of HIV infection, significantly decreased following the initiation of antiretroviral therapy (ART), and most importantly, enriched in normal resting memory B cells (RM) when HIV viremia and immune activation are controlled either naturally or as a result of ART. These HIV-specific B cells (AM and TLM) and resting memory B cells (RM) were sorted from peripheral blood mononuclear cells (PBMCs) of 6 HIV infected individuals. In addition, gp140-specific IgG+ B cells were sorted from individuals with either a strong (n= 6) or weak (n= 6) pro-resting memory profile. TaqMan gene expression assay was performed on these HIV-specific B cells and B cell subset. The array consisted of 29 genes.

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Proliferative Receptor Binding Domain (RBD)-specific CD4+ T cells correlate with neutralizing antibody levels after natural SARS-CoV-2 infection and are induced following vaccination

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