Abstract
Polysaccharide A (PSA), a capsular carbohydrate from the commensal gut bacteria Bacteroides fragilis, has been shown to possess both potent T cell-dependent pro- and anti-inflammatory properties. PSA is able to induce abscess and adhesion formation in sepsis models, but can also inhibit asthma, inflammatory bowel disease (IBD) and experimental autoimmune encephalomyelitis (EAE) through MHCII-dependent activation of CD4+ T cells. Yet, despite decades of study, the ability of PSA to balance both these pro- and anti-inflammatory responses remains poorly understood. Here, we utilized an unbiased systems immunology approach consisting of RNAseq transcriptomics, high-throughput flow cytometry, and Luminex analysis to characterize the full impact of PSA-mediated stimulation of CD4+ T cells. We found that exposure to PSA resulted in the upregulation and secretion of IFNγ, TNFα, IL-6, and CXCL10, consistent with an interferon responsive gene (IRG) signature. Importantly, PSA stimulation also led to expression of immune checkpoint markers Lag3, Tim3, and, especially, PD1, which were also enriched and sustained in the gut associated lymphoid tissue of PSA-exposed mice. Taken together, PSA responding cells display an unusual mixture of pro-inflammatory cytokines and anti-inflammatory surface receptors, consistent with the ability to both cause and inhibit inflammatory disease.
Highlights
Humans have evolved a complex relationship with colonizing bacteria in which the bacteria and their components play a key role in establishing tolerance and maintaining homeostasis
We found that polysaccharide A (PSA) induces the upregulation and expression of numerous immunological genes and molecules associated with an interferon responsive gene (IRG) signature, as well as transcription factors such as T-bet, signal transducer and activator of transcription (STAT) 1, and STAT4 which are associated with a T helper type I (Th1) phenotype [23, 24]
Using the least stringent analyses allowing for any significant (p < 0.05) non-zero (>0 fold log2CPM) change incorporating a false discovery rate (FDR) of
Summary
Humans have evolved a complex relationship with colonizing bacteria in which the bacteria and their components play a key role in establishing tolerance and maintaining homeostasis. Bacteroides fragilis is a gram negative and naturally occurring member of the normal human microbiota and has been robustly demonstrated to have both pro- [10] and anti-inflammatory [7, 11, 12] effects in rodents. This activity is mediated primarily by its capsular carbohydrate polysaccharide A (PSA) through its ability to elicit a strong T cell response [13] following processing via TLR2-stimulated nitric oxide production [14] and subsequent presentation by canonical class II MHC (MHCII) in a glycosylation-dependent fashion [15, 16]. This initial discovery of an antiinflammatory role has been expanded to include the ability to protect against inflammatory models such as adhesion formation [19], asthma [11], IBD [20], and EAE [7]
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