Dendiritc cells (DCs) play a vital role in initiating protective immune responses against pathogens, but they are also implicated in the induction and maintenance of tolerance. These diverse functions of DCs are most apparent within the gastrointestinal tract where hypo-responsiveness to commensal flora and food antigens needs to be maintained, while generating efficient immune responses against pathogens. However the mechanisms by which these functions coexist are currently unclear. Resident fractalkine receptor (CX3CR1+) expressing DCs in the mucosal tract have recently has been shown to be involved in directly sampling the contents of the intestinal lumen through extension of transepithelial dendrite and express a tolerogenic phenotype under steady state conditions. However, it is not known if these DCs are directly involved in inducing T cell tolerance to the luminal antigens they sample. The inability to mimic the complex milieu that these DCs encounter within the mucosal tract, in vitro to study their function, makes it difficult to address many of these questions by conventional techniques. This proposal utilizes deep tissue imaging by multiphoton microscopy to directly assess the function of CX3CR1+ DCs in situ. The antigen presentation by fluorescently tagged DCs and antigen-specific T cells following infection with recombinant antigen-expressing bacteria that model commensal flora (E.coli-OVA) will be used to determine if CX3CR1+ DCs are directly involved in the induction of tolerogenic T cell responses. A second objective of this proposal is to determine if the function of CX3CR1+ DCs is altered during an inflammatory response induced following pathogen infection. A co-infection model with pathogenic S. typhimurium and E.coli Ova where ovalbumin expression is limited to E.coli will be used to address this question. Such a model will allow tracking of antigen specific responses to a """"""""commensal- like"""""""" antigen during inflammatory conditions. As CX3CR1+ DCs are continually sampling commensal bacteria and food antigens, plasticity in their function during an inflammatory response could play a role in the breakdown of oral tolerance.
The current studies will reveal if the resident CX3CR1+ DC form a functionally important arm of the mucosal innate immune cell machinery that maintains oral tolerance, which is vital for preventing adverse immune responses against food antigens and commensals. In addition, we will determine if plasticity of the CX3CR1+ DC functional response contributes to the breakdown of oral tolerance under inflammatory conditions, potentially identifying them as targets for future therapeutics to treat food allergies and inflammatory bowel diseases.
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