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1.  CxCL10/CxCR3-mediated Responses Promote Immunity to Respiratory Syncytial Virus Infection by Augmenting Dendritic Cell and CD8+ T Cell Efficacy 
European journal of immunology  2008;38(8):2168-2179.
The induction of inflammatory cytokines during respiratory viral infections contributes to both disease pathogenesis and resolution. The present studies investigated the role of the chemokine CxCL10 and its specific receptor, CxCR3, in the host response to pulmonary respiratory syncytial virus (RSV) infection. Antibody-mediated neutralization of CxCL10 resulted in a significant increase in disease pathogenesis, including airway hyperresponsiveness (AHR), mucus gene expression, and impaired viral clearance. When the pulmonary cytokine levels were examined, only type I IFN and IL-12p70 were significantly reduced. These latter observations were reflected in reduced dendritic cell (DC) numbers and DC maturation in the lungs of RSV-infected mice treated with anti-CxCL10. Neutralization of the only known receptor for CxCL10, CxCR3, resulted in similar increases in pathogenic responses. When bone marrow-derived DC (BMDC) were incubated with CxCL10 and RSV, an upregulation of type I IFN was observed. In addition, T lymphocytes were also examined and a significant decrease in the number of RSV M2 peptide-specific CD8+ T cells was identified. These findings highlight a previously unappreciated role for the CXCL10:CXCR3 signaling axis in RSV-infected animals by recruiting virus-specific T cells into the lung and promoting viral clearance.
doi:10.1002/eji.200838155
PMCID: PMC2743117  PMID: 18624292
Rodent; Lung; Dendritic Cells; Chemokines; Cytokines
2.  Autophagy-mediated DC activation is essential for innate cytokine production and APC function with Respiratory Syncytial Virus responses 
The regulation of innate immune responses during viral infection is a crucial step to promote anti-viralreactions. Recent studies have drawn attention to a strong relationship of pathogen associated molecular patterns (PAMP) recognition with autophagy for activation of APC function. Our initial observations indicated that autophagosomes formed in response to RSV infection of DC. To further investigate whether RSV-induced DC activation and innate cytokine production was associated with autophagy, we utilized several methods to block autophagosome formation. Using 3-MA,siRNA inhibition of LC3,or Beclin +/- mouse derived DC,studies establisheda relationship between RSV-induced autophagy and enhanced type I IFN, TNF, IL-6, and IL-12p40expression. Moreover, autophagosome formation induced by starvation also promoted innate cytokine expression in DC. The induction of starvation-induced autophagy in combination with RSV infection synergistically enhanced DC cytokine expressionthat was blocked by an autophagy inhibitor. The latter synergistic responses were differentially altered in DC from MyD88-/- and TRIF-/-mice supporting the concept of autophagy-mediated TLR signaling. In addition, blockade of autophagy in RSV-infected DC inhibited the maturation of DCs as assessed by MHC Class II and co-stimulatory molecule expression. Subsequently, we demonstrated that inhibition of autophagy in DCsused to stimulateprimary ovalbumin-induced and secondary RSV-infected responses significantly attenuatedcytokine production by CD4+ T cells. Thus, these studies have outlined that autophagy in DC afterRSV infection isa crucial mechanism for driving innate cytokine productionleading to alteredacquired immune responses.
doi:10.4049/jimmunol.1100524
PMCID: PMC3186849  PMID: 21911604
3.  B Cell Antigen Presentation Promotes Th2 Responses and Immunopathology during Chronic Allergic Lung Disease 
PLoS ONE  2008;3(9):e3129.
Background
The role of B cells in allergic asthma remains undefined. One mechanism by which B cells clearly contribute to allergic disease is via the production of specific immunoglobulin, and especially IgE. Cognate interactions with specific T cells result in T cell help for B cells, resulting in differentiation and immunoglobulin secretion. Proximal to (and required for) T cell-dependent immunoglobulin production, however, is antigen presentation by B cells. While interaction with T cells clearly has implications for B cell function and differentiation, this study investigated the role that B cells have in shaping the T cell response during chronic allergic lung disease.
Methodology/Principal Findings
In these studies, we used a clinically relevant mouse model of chronic allergic lung disease to study the role of B cells and B cell antigen presentation in this disease. In these studies we present several novel findings: 1) Lung B cells from chronically allergen challenged mice up-regulated MHC II and costimulatory molecules CD40, CD80 and CD86. 2) Using in vitro studies, B cells from the lungs of allergen challenged mice could present antigen to T cells, as assessed by T cell proliferation and the preferential production of Th2 cytokines. 3) Following chronic allergen challenge, the levels of Th2 cytokines IL-4 and IL-5 in the lungs and airways were significantly attenuated in B cell −/− mice, relative to controls. 4) B cell driven Th2 responses and mucus hyper secretion in the lungs were dependent upon MHC II expression by B cells.
Conclusions/Significance
Collectively, these results provide evidence for antigen presentation as a novel mechanism by which B cells contribute to chronic allergic disease. These findings give new insight into the mechanisms by which B cells promote asthma and other chronic diseases.
doi:10.1371/journal.pone.0003129
PMCID: PMC2518863  PMID: 18769622
4.  The Balance between Plasmacytoid DC versus Conventional DC Determines Pulmonary Immunity to Virus Infections 
PLoS ONE  2008;3(3):e1720.
Background
Respiratory syncytial virus (RSV) infects nearly all infants by age 2 and is a leading cause of bronchiolitis. RSV may employ several mechanisms to induce immune dysregulation, including dendritic cell (DC) modulation during the immune response to RSV.
Methods and Findings
Expansion of cDC and pDC by Flt3L treatment promoted an anti-viral response with reduced pathophysiology characterized by decreased airway hyperreactivity, reduced Th2 cytokines, increased Th1 cytokines, and a reduction in airway inflammation and mucus overexpression. These protective aspects of DC expansion could be completely reversed by depleting pDCs during the RSV infection. Expansion of DCs by Flt3L treatment enhanced in CD8+ T cell responses, which was reversed by depletion of pDC.
Conclusions
These results indicate that a balance between cDC and pDC in the lung and its lymph nodes is crucial for the outcome of a pulmonary infection. Increased pDC numbers induced by Flt3L treatment have a protective impact on the nature of the overall immune environment.
doi:10.1371/journal.pone.0001720
PMCID: PMC2249704  PMID: 18320041
5.  Diversity of the T-Cell Response to Pulmonary Cryptococcus neoformans Infection  
Infection and Immunity  2006;74(8):4538-4548.
Cell-mediated immunity plays an important role in immunity to the pathogenic fungus Cryptococcus neoformans. However, the antigen specificity of the T-cell response to C. neoformans remains largely unknown. In this study, we used two approaches to determine the antigen specificity of the T-cell response to C. neoformans. We report here that a diverse T-cell receptor (TCR) Vβ repertoire was maintained throughout the primary response to pulmonary C. neoformans infection in immunocompetent mice. CD4+ T-cell deficiency resulted in relative expansion of all CD8+ T-cell subsets. During a secondary immune response, preferential usage of a TCR Vβ subset in CD4+ T cells occurred in single individuals, but the preferences were “private” and not shared between individuals. Both CD4+ and CD8+ T cells from the secondary lymphoid tissues of immunized mice proliferated in response to a variety of C. neoformans antigens, including heat-killed whole C. neoformans, culture filtrate antigen, C. neoformans lysate, and purified cryptococcal mannoprotein. CD4+ and CD8+ T cells from the secondary lymphoid tissues of mice undergoing a primary response to C. neoformans proliferated in response to C. neoformans lysate. In response to stimulation with C. neoformans lysate, lung CD4+ and CD8+ T cells produced the effector cytokines tumor necrosis factor alpha and gamma interferon. These results demonstrate that a diverse T-cell response is generated in response to pulmonary C. neoformans infection.
doi:10.1128/IAI.00080-06
PMCID: PMC1539621  PMID: 16861640
6.  Macrophage Inflammatory Protein 1α/CCL3 Is Required for Clearance of an Acute Klebsiella pneumoniae Pulmonary Infection 
Infection and Immunity  2001;69(10):6364-6369.
The objective of these studies was to determine the role of macrophage inflammatory protein 1α/CCL3 in pulmonary host defense during Klebsiella pneumoniae infection. Following intratracheal inoculation, 7-day survival of CCL3−/− mice was less than 10%, compared to 60% for CCL3+/+ mice. Survival of CCR5−/− mice was equivalent to that of controls, indicating that the enhanced susceptibility of CCL3−/− mice to K. pneumoniae is mediated via another CCL3 receptor, presumably CCR1. At day 3, CFU burden in the lungs of CCL3−/− mice was 800-fold higher than in CCL3+/+ mice, demonstrating that CCL3 is critical for control of bacterial growth in the lung. Surprisingly, CCL3−/− mice had no differences in the recruitment of monocytes/macrophages and even showed enhanced neutrophil recruitment at days 1, 2, and 3 postinfection, compared to CCL3+/+ mice. Therefore, the defect in clearance was not due to insufficient recruitment of leukocytes. No significant differences in cytokine levels of monocyte chemoattractant protein 1 (MCP-1), interleukin 12, gamma interferon, or tumor necrosis factor alpha in lung lavages were found between CCL3+/+ and CCL3−/− mice. CCL3−/− alveolar macrophages were found to have significantly lower phagocytic activity toward K. pneumoniae than CCL3+/+ alveolar macrophages. These findings demonstrate that CCL3 production is critical for activation of alveolar macrophages to control the pulmonary growth of the gram-negative bacterium K. pneumoniae.
doi:10.1128/IAI.69.10.6364-6369.2001
PMCID: PMC98771  PMID: 11553580

Results 1-6 (6)