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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:The physiological function of the immune system and the response to therapeutic immunomodulators may be sensitive to combinatorial cytokine micro-environments that shape the responses of specific immune cells. Previous work shows that paracrine cytokines released by virus-infected human dendritic cells (DC) can dictate the maturation state of naM-CM-/ve DCs. To understand the effects of paracrine signaling, we systematically studied the effects of combinations cytokines in this complex mixture in generating an antiviral state. After naM-CM-/ve DCs were exposed to either IFNM-NM-2 or to paracrine signaling released by DCs infected by Newcastle Disease Virus (NDV), microarray analysis revealed a large number of genes that were differently regulated by the DC-secreted paracrine signaling. In order to identify the cytokine mechanisms involved, we identified 20 cytokines secreted by NDV infected DCs for which the corresponding receptor gene is expressed in naM-CM-/ve DCs. By exposing cells to all combinations of 19 cytokines (leave-one-out studies) we identified 5 cytokines (IFNM-NM-2, TNFM-NM-1, IL-1M-oM-^AM-", TNFSF15 and IL28) as candidates for regulating DC maturation markers. Subsequent experiments identified IFNM-NM-2, TNFM-NM-1 and IL1M-oM-^AM-" as the major synergistic contributors to this antiviral state. This finding was supported by infection studies in vitro, by T cell activation studies and by in vivo infection studies in mouse. Combination of cytokines can cause response states in DCs that differ from those achieved by the individual cytokines alone. These results suggest that the cytokine microenvironment may act via a combinatorial code to direct the response state of specific immune cells. Further elucidation of this code may provide insight into responses to infection and neoplasia as well as guide the development of combinatorial cytokine immunomodulation for infectious, autoimmune and immunosurveillance-related diseases. Cells exposed to the supernatant of NDV infected cells were compared to NDV infected cells, IFNM-NM-2 treated cells and naM-CM-/ve dendritic cells after 8 hours.

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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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