The lung Is a unique epithelial surface at which inhaled particles, be they inert, bacteria or viral, are trapped in very close proximity to the bloodstream and in a filigree of epithelial surfaces. This presents unique spatial challenges for the T cells of the immune system to properly survey these antigens. Like many epithelial tissues, a selection of Immune macrophage and dendritic cells are poised within and beneath the surface to engulf and either neutralize, or to induce a more profound response to the Insult. During inflammatory insults including those of allergic but also bacterial or viral insults, the lung microenvironment physically changes. This new Project 2 will use live-imaging of viable lung and airways to determine how antigens traffic Into the lung and subsequently activate T cells, focusing the majority of effort upon a mouse model of asthma. The primary Issue being addressed is how inflammatory environments create a feedback loop that promotes accelerated immune responses and thus an enhanced inflammatory environment. We hypothesize that inflammation in the lung airway and aveolae creates a hyperreactive milieu for T lymphocyte priming. This milieu in turn is highly facilltative for synaptic interactions and thus increased production of lung remodeling factors Including cytokines. We propose that there are three distinct components of this. First, that there is a shift in the numbers, localization, antigen uptake and trafficking features between tolerizing phagocytic macrophages and highly immunogenic dendritic cells. The features of inflammatory antigens as well as the features of a remodeled milieu are both proposed to be directly responsible for the shift in the nature of APC which interact with T cells. Second, a shift In local polyclonal and antigen-specific regulatory T cells,modulated in part by the changes in APC population, subsequently modulates the activation of T cells. Finally, that T cells and their APC are modulated by airway remodeling and inflammation induced by agents such as Mycoplasma pulmonis or mast cell depletion. Thus, inflammation creates a fertile stimulatory ground for responses to inhaled antigens.

Public Health Relevance

The lung is the site of allergic as well as protective immune responses. Yet, we have little understanding of how antigen presentation leads to discrimination within this vital organ. Our studies will examine how this occurs spatially and temporally. The project will interface with Project 1 and 3 of this PPG by virtue of a common focus on remodeling factors that drive changes in the lung microenvironment during inflammation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL024136-34
Application #
8451348
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
34
Fiscal Year
2013
Total Cost
$312,647
Indirect Cost
$109,534
Name
University of California San Francisco
Department
Type
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Greenland, J R; Jewell, N P; Gottschall, M et al. (2014) Bronchoalveolar lavage cell immunophenotyping facilitates diagnosis of lung allograft rejection. Am J Transplant 14:831-40
Baluk, Peter; Adams, Alicia; Phillips, Keeley et al. (2014) Preferential lymphatic growth in bronchus-associated lymphoid tissue in sustained lung inflammation. Am J Pathol 184:1577-92
Sutherland, Rachel E; Barry, Sophia S; Olsen, Joanna S et al. (2014) Dipeptidyl peptidase I controls survival from Klebsiella pneumoniae lung infection by processing surfactant protein D. Biochem Biophys Res Commun 450:818-23
Gérard, Audrey; Patino-Lopez, Genaro; Beemiller, Peter et al. (2014) Detection of rare antigen-presenting cells through T cell-intrinsic meandering motility, mediated by Myo1g. Cell 158:492-505
Ortiz-Muñoz, Guadalupe; Mallavia, Beñat; Bins, Adriaan et al. (2014) Aspirin-triggered 15-epi-lipoxin A4 regulates neutrophil-platelet aggregation and attenuates acute lung injury in mice. Blood 124:2625-34
Giannotta, Monica; Benedetti, Sara; Tedesco, Francesco Saverio et al. (2014) Targeting endothelial junctional adhesion molecule-A/ EPAC/ Rap-1 axis as a novel strategy to increase stem cell engraftment in dystrophic muscles. EMBO Mol Med 6:239-58
Broz, Miranda L; Binnewies, Mikhail; Boldajipour, Bijan et al. (2014) Dissecting the tumor myeloid compartment reveals rare activating antigen-presenting cells critical for T cell immunity. Cancer Cell 26:638-52
Patnode, Michael L; Bando, Jennifer K; Krummel, Matthew F et al. (2014) Leukotriene B4 amplifies eosinophil accumulation in response to nematodes. J Exp Med 211:1281-8
Baluk, Peter; Phillips, Keeley; Yao, Li-Chin et al. (2014) Neutrophil dependence of vascular remodeling after Mycoplasma infection of mouse airways. Am J Pathol 184:1877-89
Lelkes, Efrat; Headley, Mark B; Thornton, Emily E et al. (2014) The spatiotemporal cellular dynamics of lung immunity. Trends Immunol 35:379-86

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