Innate Immunity In Allergic and Non-Allergic Responses

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DESCRIPTION (provided by applicant): The recent increase in asthma incidence compels examination of distinct, modifiable pathways in allergic responses. We propose that Toll-like receptor 2 (TLR2) may be a critical target for modification in allergic responses. We focus on the role of TLR2 (a receptor for common pulmonary exposures including gram positive and negative bacteria) in the modulation of allergic responses. Experimental evidence from our preliminary data demonstrates that TLR2 pathways modify allergic responses in a well-characterized murine model. Stimulation of TLR2 signaling by the TLR2 ligand peptidoglycan (Ppg) or PamSCys decreases allergic responses and mice deficient in TLR2 have increased allergic responses. This data supports our major postulate that TLR2 signaling pathways play a crucial role in the suppression of allergic responses. To dissect TLR2 mediated suppression of allergic responses, we focus on T cells, a cell type we have previously shown to be critical in regulating allergic responses. In contrast to other innate molecules, the TLR2 mediated suppression of allergic responses does not result in increased Thl responses. This data leads us to hypothesize involvement of other T cell subsets, including regulatory (Treg), T cells known to express TLR2. Treg cells can inhibit T cell activation and are known to secrete IL-10, a potent immunosuppressive cytokine. Our preliminary data demonstrates that administration of Ppg allergen to sensitized mice increases IL- 10 levels while decreasing allergic responses. TLR2 signaling in Treg cells may provide a potentially important pathway in the suppression of allergic responses. In Aim 1, we will examine critical pathways for TLR2 signaling in terms of timing, cytokines and effects of the TLR2 ligand, Ppg. In Aim 2, we will investigate whether TLR2 modulation of allergic inflammation is mediated by T cell dependent interactions including Tregs. In Aims 3 and 4, we focus on the effect of TLR2 signals on markers of Tregs, and allergic inflammation. The fundamental strategy is to examine the contribution of the key molecule TLR2 in the modulation of allergic immune responses.