Unveiling Dendritic Cell Regulatory Program in Polymicrobial Sepsis: Immune Spatiotemporal Profiling

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Summary

Amid the prevalent immunosuppression observed in septic patients, the broader landscape of the immune response to sepsis remains under-explored. Their study utilized single-cell RNA sequencing on a CLP mouse model, revealing considerable variations in canonical immune cells during sepsis across key tissue sites. One significant finding was the identification of a unique dendritic cell subcluster—termed mregDCs—akin to those described in cancer research. These mregDCs were found to strongly engage naïve CD4+ T cells and encourage their transformation into regulatory T cells. This phenomenon seems linked to specific signaling pathways activated within the first day of septic challenge. Furthermore, parallels were drawn with human sepsis data from a recent COVID-19 patient study.

Research Criteria

The study's goal was to give a comprehensive understanding of the host immunological response to sepsis. The majority of past research on immunosuppression in sepsis has concentrated on a single type of immune cell. On a cecal ligation and puncture (CLP) mouse model, this study used multi-compartment, single-cell RNA sequencing (scRNA-seq) to examine heterogeneity within immune cell subsets during sepsis progression.

Fig.1 Experimental design¹.

Sample Type

Spleens, bone marrows, and PBMCs from a cecal ligation and puncture (CLP) mouse model were employed for single-cell studies. The researchers used scRNA-seq on immune-relevant tissue sites such as T, B, natural killer (NK), and myeloid cells.

Result—Immune Cell Subtype Analysis in the Course of Sepsis

Researchers conducted a detailed analysis of various immune cell types. T lymphocytes were categorized into 17 subclusters, with notable findings including the sustained representation of naïve CD4+ T cells up to 24 hours post-sepsis and an increase in regulatory T cells (Treg) after sepsis onset. B lymphocytes were grouped into 18 subclusters, with mature B cells showing a decline in the peripheral blood after septic challenge, while immature B cells expanded, suggesting hindered B cell maturation during sepsis. Myeloid cells were divided into 21 subpopulations, with significant changes observed in splenic monocytes and dendritic cells post-sepsis. Additionally, NK cells and cycling cells were also analyzed, revealing alterations in their subclusters. Overall, the findings underscore the profound impact of sepsis on the immune system, with various cell types undergoing significant shifts in response to the condition.

Fig.2 T, B, and myeloid cell subtype studies based on single-cell gene expression¹.

Result—mregDCs have Immunoregulatory as well as Immunogenic Properties

During the course of sepsis, the prevalence of mregDCs, a distinct dendritic cell type, surged notably within 24 hours, especially within the cDC2 subset, as evidenced by flow cytometry and gene signature identification. The mregDC population was significantly reduced in certain genetically altered mice, hinting at a genetic influence over their emergence. When co-cultured with naïve CD4+ T cells, mregDCs notably increased the secretion of interleukins IL-2 and IL-10. Moreover, mregDCs were adept at activating and proliferating these T cells and guiding their differentiation into regulatory T cells. These findings suggest mregDCs, induced during sepsis, may have a dual role in shaping immune responses, both invigorating and modulating CD4+ T cell functions.

Fig.3 Sepsis-induced mregDCs have distinct transcriptional fingerprints¹.

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Reference

1. Yao, Ren-qi, et al. "Single-cell transcriptome profiling of the immune space-time landscape reveals dendritic cell regulatory program in polymicrobial sepsis." Theranostics 12.10 (2022): 4606.