Lung dendritic cells imprint T cell lung homing and promote lung immunity through the chemokine receptor CCR4.

T cell trafficking into the lung is critical for lung immunity, but the mechanisms that mediate T cell lung homing are not well understood. Here, we show that lung dendritic cells (DCs) imprint T cell lung homing, as lung DC-activated T cells traffic more efficiently into the lung in response to inhaled antigen and at homeostasis compared with T cells activated by DCs from other tissues. Consequently, lung DC-imprinted T cells protect against influenza more effectively than do gut and skin DC-imprinted T cells. Lung DCs imprint the expression of CCR4 on T cells, and CCR4 contributes to T cell lung imprinting. Lung DC-activated, CCR4-deficient T cells fail to traffic into the lung as efficiently and to protect against influenza as effectively as lung DC-activated, CCR4-sufficient T cells. Thus, lung DCs imprint T cell lung homing and promote lung immunity in part through CCR4.

Humoral immune deficiency and hemifacial microsomia seen in one family.

We present a patient with hemifacial microsomia and immune deficiency. The patient is a 5-year-old with grade III microtia and Pruzansky type I right mandibular hypoplasia. She developed 25 pulmonary infections in 3 years, required hospitalization every 6 weeks to receive antibiotics, and experienced recurrent herpes stomatitis and esophagitis, staphylococcal bacteremia, urinary tract, sinus, and ear infections. She had low total IgG, IgG1, IgG2, IgA, and anti-pneumococcal antibody levels. She was unable to maintain protective pneumococcal titers following vaccination. The patient's 7-year-old sister also suffered from recurrent infections, had a left facial skin tag, and a left arachnoid cyst. We conclude that immune deficiency can occur in association with hemifacial microsomia.

The emergence of basophils as antigen-presenting cells in Th2 inflammatory responses.

Basophils gain prominence in Th2 inflammatory responses with the discovery that they function as antigen-presenting cells and are sufficient to drive Th2 cell differentiation.

Endotoxin augmented antigen-induced Th1 cell trafficking amplifies airway neutrophilic inflammation.

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 Galphai-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-gamma 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.

Contribution of CCR4 and CCR8 to antigen-specific T(H)2 cell trafficking in allergic pulmonary inflammation.

BACKGROUND: Recruitment of antigen-specific T(H)2 cells into the lung is critical for the development of allergic airway inflammation. Although CCR4 and CCR8 are preferentially expressed on T(H)2 cells and CCR4, CCR8, and CXCR3 ligands are increased in asthma, the specific relative contribution of these receptors to antigen-specific T(H)2 cell trafficking into the allergic lung is not known. OBJECTIVE: To determine the relative contribution of the chemokine receptors CCR4, CCR8, and CXCR3 to antigen-specific T(H)2 cell trafficking in a murine model of allergic pulmonary inflammation. METHODS: We used adoptive transfer experiments to compare the trafficking of wild-type antigen-specific T(H)2 cells with antigen-specific T(H)2 cells deficient in CCR4, CCR8, or CXCR3. RESULTS: CCR4-deficient antigen-specific T(H)2 cells failed to traffic efficiently into the lung and the airways. In contrast, CCR8-deficient antigen-specific T(H)2 cells accumulated in these sites. Trafficking of CXCR3-deficient antigen-specific T(H)2 cells and CCR4-deficient and CCR8-deficient antigen-specific T(H)1 cells were comparable to their wild-type counterparts. Approximately 60% of IL-4-producing antigen-specific T cells expressed CCR4. Disruption of CCR4-mediated antigen-specific T(H)2 cell trafficking decreased the levels of T(H)2-type cytokines in the airways and reduced airway eosinophilia and mucus production. CONCLUSIONS: Our study demonstrates that CCR4 is required for the efficient entry of antigen-specific T(H)2 cells into the lung and the airways in a murine model of allergic pulmonary inflammation.

Dose-response studies of fluticasone propionate and budesonide: classification based on asthma severity.

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.

STAT1 in peripheral tissue differentially regulates homing of antigen-specific Th1 and Th2 cells.

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 Th1 cells 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.

An animal model for ultrasound lung imaging.

In the past decade, a number of clinical investigators have used ultrasound (US) to image the lung during video-assisted thoracoscopic surgery (VATS). In contrast, animal studies have shown prohibitively high attenuation levels in the lung, incompatible with the ability to image the lung. We hypothesized that the use of anesthesia during VATS augments lung collapse upon exposure to atmospheric pressure; thus, making US lung imaging possible. To test this hypothesis, we compared the effect of two commonly used anesthetic protocols on our ability to image 200 microL of US gel injected in rabbit lungs using a pulse echo transducer at 13 MHz. The anesthetic protocol, using acepromazine, ketamine and isoflurane, allowed US lung imaging in rabbits. It is concluded that US at 13 MHz can detect 200 microL of US gel injected into the lung parenchyma in a rabbit model.

Acoustic attenuation properties of the lung: an open question.

Between 1961 and 1986, a number of investigators studied the propagation properties of ultrasound (US) in the lungs. These studies revealed high attenuation levels in the lung tissue at all levels of lung inflation. In contrast, some clinical investigators have, in the past decade, used US at 5 to 7.5 MHz to penetrate the collapsed lung effectively during intraoperative thoracic ultrasonography. There is a discrepancy between these clinical imaging results and the high attenuation levels found in the earlier studies of US propagation in the lungs. We studied the attenuation of US in the lungs with an ultrasonic analyzer, designed for highly attenuating materials, and utilizing linear sweep-based transmission measurements. Our data also revealed high attenuation levels at various low levels of lung inflation, inconsistent with the findings of intraoperative thoracic ultrasonography. These results imply that the US attenuation properties of the lung are far from accurately established.