Lipopolysaccharide-enhanced, Toll-like Receptor 4–dependent T Helper Cell Type 2 Responses to Inhaled Antigen

Allergic asthma is an inflammatory lung disease initiated and directed by T helper cells type 2 (Th2). The mechanism involved in generation of Th2 responses to inert inhaled antigens, however, is unknown. Epidemiological evidence suggests that exposure to lipopolysaccharide (LPS) or other microbial products can influence the development and severity of asthma. However, the mechanism by which LPS influences asthma pathogenesis remains undefined. Although it is known that signaling through Toll-like receptors (TLR) is required for adaptive T helper cell type 1 (Th1) responses, it is unclear if TLRs are needed for Th2 priming. Here, we report that low level inhaled LPS signaling through TLR4 is necessary to induce Th2 responses to inhaled antigens in a mouse model of allergic sensitization. The mechanism by which LPS signaling results in Th2 sensitization involves the activation of antigen-containing dendritic cells. In contrast to low levels, inhalation of high levels of LPS with antigen results in Th1 responses. These studies suggest that the level of LPS exposure can determine the type of inflammatory response generated and provide a potential mechanistic explanation of epidemiological data on endotoxin exposure and asthma prevalence

Differential analysis of RNA-seq incorporating quantification uncertainty

We describe sleuth (http://pachterlab.github.io/sleuth), a method for the differential analysis of gene expression data that utilizes bootstrapping in conjunction with response error linear modeling to decouple biological variance from inferential variance. sleuth is implemented in an interactive shiny app that utilizes kallisto quantifications and bootstraps for fast and accurate analysis of data from RNA-seq experiments

Innate Immune Control of Pulmonary Dendritic Cell Trafficking

Dendritic cells (DC) are potent antigen-presenting cells that are essential for initiating adaptive immune responses. Residing within the airway mucosa, pulmonary DC continually sample the antigenic content of inhaled air and migrate to draining lymph nodes, where they present these antigens to naive T cells. The migratory patterns of pulmonary DC are highly dependent upon inflammatory conditions in the lung. Under steady-state, or non-inflammatory, conditions, pulmonary DC undergo slow but constitutive migration to draining lymph nodes, where they remain for several days and confer antigen-specific tolerance. With the onset of pulmonary inflammation, airway DC trafficking increases dramatically, and these cells rapidly accumulate within draining lymph nodes. However, within a few days, the number of airway-derived DC in lymph nodes stabilizes or declines, even in the face of ongoing pulmonary inflammation. Here, we summarize current understanding of the molecular and cellular mechanisms underlying pulmonary DC trafficking to the lymph node and the recruitment of DC precurors to the lung. It is hoped that an improved understanding of these mechanisms will lead to novel DC-mediated therapeutic strategies to treat immune-related pulmonary disease