Lung dendritic cells promote lung homing by T cells in part via up-regulation of chemokine receptor CCR4.

Background-Recruitment of antigen-specific Th2 cells into the lung is critical for the development of allergic airway inflammation. Although CCR4 and CCR8 are preferentially expressed on Th2 cells and CCR4, CCR8 and CXCR3 ligands are increased in asthma, the specific relative contribution of these receptors to antigen-specific Th2 cell trafficking into the allergic lung is not known.

Th1 and Th2 effector CD4+ T cells orchestrate distinct counterregulatory biological responses. To deliver effective tissue Th1- and Th2-type responses, Th1 and Th2 cell recruitment into tissue must be differentially regulated. We show that tissue-derived STAT1 controls the trafficking of adoptively transferred, Ag-specific, wild-type Th1 cells into the lung. Trafficking of Th1 and Th2 cells is differentially regulated as STAT6, which regulates Th2 cell trafficking, had no effect on the trafficking of Th1 cells and STAT1 deficiency did not alter Th2 cell trafficking. We demonstrate that STAT1 control of Th1 cell trafficking is not mediated through T-bet. STAT1 controls the recruitment of Th1cells through the induction of CXCL9, CXCL10, CXCL11, and CXCL16, whose expression levels in the lung were markedly decreased in STAT1−/− mice. CXCL10 replacement partially restored Th1 cell trafficking in STAT1-deficient mice in vivo, and deficiency in CXCR3, the receptor for CXCL9, CXCL10, and CXCL11, impaired the trafficking of adoptively transferred Th1 cells in wild-type mice. Our work identifies that STAT1 in peripheral tissue regulates the homing of Ag-specific Th1 cells through the induction of a distinct subset of chemokines and establishes that Th1 and Th2 cell trafficking is differentially controlled in vivo by STAT1 and STAT6, respectively.

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CD4+ Th1 cells play a critical role in orchestrating host defense against pathogens and in the pathogenesis of many immune-mediated diseases. The control of Th1 cell trafficking into sites of infection and inflammation is an important determinant of Th1 cell function. We have previously shown that trafficking of adoptively transferred Ag-specific Th1 cells into the lung following airway Ag challenge depends on CXCR3 expression on Th1 cells and STAT1-inducible CXCR3 ligands in the lung. In this study, we show that LPS alters the mechanisms of Th1 cell recruitment. After a single intranasal dose of LPS, trafficking of adoptively transferred Ag-specific Th1 cell into the lung in response to airway Ag challenges was no longer dependent on CXCR3 and its ligands and instead was mediated through additional Gαi-coupled chemoattractant receptor pathways, including CCR5. In addition, LPS markedly increased the magnitude of Ag-specific Th1 cell homing into the airways following airway Ag challenges. The increased trafficking of Ag-activated Th1 cells, in turn, dramatically amplified LPS-induced airway neutrophilic infiltration by maintaining high levels of the neutrophil active chemokines, KC and MIP-2, through an IFN-γ dependent mechanism. Therefore, LPS increases Ag-specific Th1 cell trafficking into the airways and Ag-specific Th1 cells amplify the airway neutrophilic inflammatory response initiated by LPS. This reciprocal interaction between LPS and Ag-activated Th1 cells represents a collaborative connection between the innate and adaptive arms of the immune system.

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There are discrepancies in the results of dose-response studies of inhaled steroids. Although some studies show a dose-response relationship, others show no change in outcome with increasing the dose of inhaled steroids. These discrepancies are partly caused by the heterogeneity of dose-response studies. One area of heterogeneity is the subjects' level of asthma severity at baseline. The objective of this study was to classify dose-response studies of two widely used inhaled steroids for asthma, fluticasone propionate (FP), and budesonide (BUD), according to the subjects' level of asthma severity at baseline. A PubMed search, limited to the English language and human subjects, was conducted from January of 1983 to January of 2004, using "dose response and budesonide" (331 articles) and "dose-response and fluticasone" (211 articles). Bibliographies of selected articles were searched for more references. Articles with at least two doses of the same inhaled steroid and one objective marker of asthma were included, resulting in 29 articles for FP and 32 articles for BUD. Studies vary widely in their assessment and reporting of indicators of asthma severity and control at baseline but could be classified according to the level of steroid use at baseline as an indicator of asthma severity. Studies with all or some patients on oral steroids at baseline consistently showed a dose response. Although heterogeneity of dose-response studies make their classification and interpretation difficult, a dose response was consistently noted when all or some patients were on oral steroids at baseline.