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Dissecting the protein and transcriptional responses of human immune cells to T cell and monocyte specific activation

ABSTRACT: Single cell profiling is a powerful tool for studying the molecular and cellular (dys)function of activated peripheral blood mononuclear cells (PBMCs) in the context of disease. We combined CITE-seq with two levels of multiplexing (cell hashing and individuals? genotypes) to derive a reference database of immune cell gene/protein responses to different activation conditions. PBMCs from 10 healthy adults were profiled before and after stimulating i) T cells via anti-CD3/CD28 or ii) monocytes via LPS. By using a comprehensive antibody panel (n=39) of cell type (e.g., CD16, CD14) and cell state (e.g., CD69, CD25) markers, we discovered that all lymphocytes responded to anti-CD3/CD28 stimulation, whereas LPS specifically induced inflammation in monocytes. Pseudo-temporal analyses further revealed cell- and condition-specific heterogeneity in responses to activation that were independent of individual-specific variation. Together, these data are shared within an interactive web application (https://czi-pbmc-cite-seq.jax.org/) and will serve as a resource to guide future studies of immune cell responses.

INSTRUMENT(S): Illumina NovaSeq 6000

ORGANISM(S): Homo Sapiens

SUBMITTER: The Jackson Laboratory

PROVIDER: PRJEB40448 | EVA | 2021-01-04

REPOSITORIES: EVA

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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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Dissecting the protein and transcriptional responses of human immune cells to T cell and monocyte specific activation

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