Asthma and airway inflammatory disease has become the leading cause for ER visits in the US, a four- decade trend linked to the increasing sterility of western lifestyles and a proposed lack of early microbial antigen exposure. Gastrointestinal contact with the Bacteroides fragilis glycoantigen (GlyAg) polysaccharide A (PSA) has been shown to educate the immune system to limit the degree of inflammation in the gut. Effective immune responses upon re-exposure to an antigen is typically mediated through antigen-experienced memory T cells, whereas regulatory T (Treg) cells are known to play key roles in suppressing immune responses, generally through the secretion of immunosuppressive cytokines like IL-10. Our preliminary data show that gut exposure to PSA increases a population of antigen experienced CD4+CD45RbloTEM cells which are capable of amplifying IL-10 production in peripheral tissues upon inflammatory stimulus. Additional data demonstrates that these CD45RbloTEM cells synergistically induce IL-10 production with Tregs when co-cultured in vitro. We hypothesize that commensal microflora are linked to peripheral immunomodulation through T-cell cooperation between commensal-specific CD45RbloTEM cells and tissue-resident Tregs. In this proposal, we will (1) identify the mediator(s) by which this novel pathway of T cell T cell cooperation is capable of dampening the magnitude of antigen-specific memory responses in the periphery, and (2) establish proof-of-principle pre-clinical applications of this pathway to ameliorate experimental airway inflammation. This study will provide a novel mechanistic framework for the hygiene hypothesis, whereby communication between the microbiota in the gut and the T cell compartment links commensal products to non-specific peripheral immune quiescence resulting in reduced susceptibility to inflammation. Dissecting this process will provide a basis for the treatment of inflammatory disease and autoimmunity with oral delivery of specific bacterial glycoantigens, and may provide new T cell directed therapeutic targets for the treatment of these diseases.
The immune system is constantly exposed to bacterial products from the gut, some of which elicit potent inflammatory responses to destroy infectious microbes, and others which educate adaptive immunity resulting in immune suppression. An alteration in this balance may result in pro-inflammatory conditions being preferred, producing overly robust responses and inflammatory diseases. Recent findings have demonstrated that gut exposure to certain commensal bacterial glycoantigens (GlyAgs) have T cell-dependent immunomodulatory activity, calming the immune system. Preliminary findings suggest that PSA is able to ameliorate airway inflammation similar to asthma, providing a mechanistic connection between the gut and peripheral immunity as predicted by the Hygiene Hypothesis. Results will provide new therapeutic targets for the treatment of inflammatory disease and autoimmunity as well as a rationale for proposing naturally-occurring commensal products as drug candidates.
| Jones, Mark B (2018) IgG and leukocytes: Targets of immunomodulatory ?2,6 sialic acids. Cell Immunol 333:58-64 |
| Johnson, Jenny L; Jones, Mark B; Cobb, Brian A (2018) Polysaccharide-experienced effector T cells induce IL-10 in FoxP3+ regulatory T cells to prevent pulmonary inflammation. Glycobiology 28:50-58 |
| Jones, Mark B; Ryan, Sean O; Johnson, Jenny L et al. (2016) Dendritic cell-specific Mgat2 knockout mice show antigen presentation defects but reveal an unexpected CD11c expression pattern. Glycobiology 26:1007-1013 |
| Jones, Mark B; Oswald, Douglas M; Joshi, Smita et al. (2016) B-cell-independent sialylation of IgG. Proc Natl Acad Sci U S A 113:7207-12 |
