Polysaccharide A (PSA) derived from the human commensal Bacteroides fragilis is a symbiosis factor that stimulates immunologic development within mammalian hosts. PSA rebalances skewed systemic T helper responses and promotes T regulatory cells (Tregs). However, PSA-mediated induction of Foxp3 in humans has not been reported. In mice, PSA-generated Foxp3(+) Tregs dampen Th17 activity thereby facilitating bacterial intestinal colonization while the increased presence and function of these regulatory cells may guard against pathological organ-specific inflammation in hosts. We herein demonstrate that PSA induces expression of Foxp3 along with CD39 among naïve CD4 T cells in vitro while promoting IL-10 secretion. PSA-activated dendritic cells are essential for the mediation of this regulatory response. When cultured with isolated Foxp3(+) Tregs, PSA enriched Foxp3 expression, enhanced the frequency of CD39(+)HLA-DR(+) cells, and increased suppressive function as measured by decreased TNFα expression by LPS-stimulated monocytes. Our findings are the first to demonstrate in vitro induction of human CD4(+)Foxp3(+) T cells and enhanced suppressive function of circulating Foxp3(+) Tregs by a human commensal bacterial symbiotic factor. Use of PSA for the treatment of human autoimmune diseases, in particular multiple sclerosis and inflammatory bowel disease, may represent a new paradigm in the approach to treating autoimmune disease.
Keywords: B. fragilis, Bacteroides fragilis; Bacteroides fragilis; DC, Dendritic cell; Foxp3; GF, Germ Free; MS, Multiple sclerosis; NCD4, Naïve CD4; PBMCs, Peripheral blood mononuclear cells; PSA, Polysaccharide A; SPF, Specific pathogen free; Sp1, Streptococcus pneumoniae polysaccharide type 1; T regulatory cells; Treg, T regulatory cell; ZPS, Zwitterionic polysaccharide.; autoimmunity; commensal microbiota; dendritic cell; ectonuclease; multiple sclerosis; pDC, Plasmacytoid dendritic cell; zwitterionic polysaccharide.