Immune-mediated inflammatory diseases are a major public health issue. In the lungs, these can be triggered by exposure to environmental antigens and toxins, or by infection, and can result in severe respiratory disease and death. Defining the immunoregulatory mechanisms that normally function to prevent pulmonary inflammation is therefore key to understanding the etiology of these diseases, and for developing therapeutic strategies to boost these activities in patients. Regulatory T cells (TR) expressing the transcription factor Foxp3 play a critical role in preventing autoimmunity and limiting immune-mediated inflammation. We have shown that during type-1 inflammatory responses, Foxp3+ TR upregulate the Th1 specifying transcription factor Tbx21 (T-bet), and that T-bet expression is critical for proper TR homeostasis and function during Th1-mediated inflammation. Therefore, the goals of this proposal are to determine in detail how loss of T-bet specifically within Foxp3+ TR impacts the initiation, progression and termination of Th1 responses in models of acute and persistent lung infection in vivo (Specific Aim 1), define the cytokines and cellular signals that direct TR expression of T-bet (Specific Aim 2), and analyze at the molecular level how Foxp3 and T-bet combine to control the expression of genes involved in Th1/TR differentiation, homeostasis and function (Specific Aim 3). Together, these experiments will generate an unprecedented understanding of the molecular specialization of TR subsets during type-1 inflammation, and provide a new framework in which to understand how so-called 'master transcription factors'direct the functional differentiation of CD4+ T cell subsets.
Understanding how TR modulate Th1-mediated immune responses has clear and direct implications in the clinical application of TR for the treatment of immunolgic pulmonary diseases caused by dysregulated Th1 cell responses, such as granulomatous inflammation associated with persistent Mycobacterium tuberculosis infection, hypersensitivity pneumonitis, and chronic obstructive pulmonary disease.
|Rohani, Maryam G; Dimitrova, Elizabeth; Beppu, Andrew et al. (2018) Macrophage MMP10 Regulates TLR7-Mediated Tolerance. Front Immunol 9:2817|
|Maisel, Katharina; Merrilees, Mervyn J; Atochina-Vasserman, Elena N et al. (2018) Immune Checkpoint Ligand PD-L1 Is Upregulated in Pulmonary Lymphangioleiomyomatosis. Am J Respir Cell Mol Biol 59:723-732|
|Han, H; Roan, F; Johnston, L K et al. (2018) IL-33 promotes gastrointestinal allergy in a TSLP-independent manner. Mucosal Immunol 11:394-403|
|Evanko, Stephen P; Chan, Christina K; Johnson, Pamela Y et al. (2018) The biochemistry and immunohistochemistry of versican. Methods Cell Biol 143:261-279|
|Gaucherand, Léa; Falk, Ben A; Evanko, Stephen P et al. (2017) Crosstalk Between T Lymphocytes and Lung Fibroblasts: Generation of a Hyaluronan-Enriched Extracellular Matrix Adhesive for Monocytes. J Cell Biochem 118:2118-2130|
|Han, Hongwei; Roan, Florence; Ziegler, Steven F (2017) The atopic march: current insights into skin barrier dysfunction and epithelial cell-derived cytokines. Immunol Rev 278:116-130|
|Kang, Inkyung; Harten, Ingrid A; Chang, Mary Y et al. (2017) Versican Deficiency Significantly Reduces Lung Inflammatory Response Induced by Polyinosine-Polycytidylic Acid Stimulation. J Biol Chem 292:51-63|
|Sheih, A; Parks, W C; Ziegler, S F (2017) GM-CSF produced by the airway epithelium is required for sensitization to cockroach allergen. Mucosal Immunol 10:705-715|
|Kashiwagi, Mariko; Hosoi, Junichi; Lai, Jen-Feng et al. (2017) Direct control of regulatory T cells by keratinocytes. Nat Immunol 18:334-343|
|Secor, Patrick R; Michaels, Lia A; Smigiel, Kate S et al. (2017) Filamentous Bacteriophage Produced by Pseudomonas aeruginosa Alters the Inflammatory Response and Promotes Noninvasive Infection In Vivo. Infect Immun 85:|
Showing the most recent 10 out of 83 publications