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.
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