Dendritic cells, Mucosal Immunity and C-type Lectins

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DESCRIPTION (provided by applicant): The oral cavity, the gut-associated immune system and the skin have in residence both commensal and pathogenic bacteria. Significant progress has been made in defining how the innate immune system recognizes and responds to pathogenic bacteria via signaling through pattern recognition receptors (PRRs). However, relatively little is known about how the innate immune system responds to commensal bacteria and how encounters with commensals influence how the immune system responds to pathogens. This proposal will address this fundamental question using oral microflora and the C-type lectin receptor family as a model system. We have selected the C-type lectin family because members of this family of receptors appear to be able to both recognize and mediate either positive or negative responses to pathogens and because we have defined three new members of this family. The well-defined oral microflora is ideal for addressing this question. We have identified several new C-type lectins designated DCAL-1, DCAL-2 and DCAL-3. DCAL-2 is restricted in its expression to antigen presenting cells and has within its cytoplasmic tail an immunoreceptor tyrosine inhibitory motif (ITIM), suggesting that it functions to inhibit DC activation. We will first test if dendritic cells (DCs) are regulated differently by periopathogenic bacteria vs. commensal oral bacteria. We will compare the ability of oral flora to induce DC maturation, expression of inflammatory and non-inflammatory cytokines and chemokines, and expression of TLR and C-type lectin receptors. We predict that commensal bacteria, unlike periopathogenic bacteria, will trigger an anti-inflammatory program. Using microarrays we will test the hypothesis that pathogenic and commensal bacteria activate in DCs distinctive 'prewired signaling patterns' under the control of distinct drivers, which affect DC functions. Next we will test if DCAL-2 inhibits dendritic cell functions alters responses to periopathogenic bacteria. We will determine if certain bacteria including oral microflora bind to and signal DCs through DCAL-2. Finally we will test if DCAL-2 plays an important role in the resistance to pathogenic bacterial infection in vivo. We will prepare and then characterize DCAL-2-deficient mice and determine if these mice are more susceptible or resistant to infection by P. gingivalis as measured by alveolar bone loss and antibody responses. This work will lead to better understanding about how microflora can affect DCs.