Antigen presenting cell response to polysaccharide A is characterized by the generation of anti-inflammatory macrophages

Author:

Zhou Julie Y1,Zhou David2,Telfer Kevin1,Reynero Kalob1,Jones Mark B1,Hambor John3,Cobb Brian A1ORCID

Affiliation:

1. Department of Pathology, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106-7288, USA

2. Department of Computer Science, Arizona State University, 1151 S. Forest Avenue, Tempe, AZ 85281, USA

3. Research Beyond Borders, Boehringer Ingelheim Pharmaceuticals, 900 Ridgebury Road, Ridgefield, CT 06877, USA

Abstract

Abstract Polysaccharide A (PSA) is the immunodominant capsular carbohydrate from the gram negative commensal microbe Bacteroides fragilis that has shown remarkable potency in ameliorating many rodent models of inflammatory disease by eliciting downstream suppressive CD4+ T cells. PSA is composed of a zwitterionic repeating unit that allows it to be processed by antigen presenting cells (APCs) and presented by MHCII in a glycosylation-dependent manner. While previous work has uncovered much about the interactions between MHCII and PSA, as well as the downstream T cell response, little is known about how PSA affects the phenotype of MHCII+ APCs, including macrophages. Here, we utilized an unbiased systems approach consisting of RNAseq transcriptomics, high-throughput flow cytometry, Luminex analysis and targeted validation experiments to characterize the impact of PSA-mediated stimulation of splenic MHCII+ cells. The data revealed that PSA potently elicited the upregulation of an alternatively activated M2 macrophage transcriptomic and cell surface signature. Cell-type-specific validation experiments further demonstrated that PSA-exposed bone marrow-derived macrophages (BMDMs) induced cell surface and intracellular markers associated with M2 macrophages compared with conventional peptide ovalbumin (ova)-exposed BMDMs. In contrast to macrophages, we also found that CD11c+ dendritic cells (DCs) upregulated the pro-T cell activation costimulatory molecule CD86 following PSA stimulation. Consistent with the divergent BMDM and DC changes, PSA-exposed DCs elicited an antigen-experienced T cell phenotype in co-cultures, whereas macrophages did not. These findings collectively demonstrate that the PSA-induced immune response is characterized by both T cell stimulation via presentation by DCs, and a previously unrecognized anti-inflammatory polarization of macrophages.

Funder

National Institutes of Health

Publisher

Oxford University Press (OUP)

Subject

Biochemistry

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