Ubiquitin-mediated degradation is activated when an E3 ubiquitin ligase transfers ubiquitin to a target protein. Nedd4 is a HECT-type E3 ubiquitin ligases, particularly relevant to T cell function. We have found that Nedd4 promotes T cell activation by decreasing levels of Cbl-b. Our hypothesis is that Nedd4 promotes T cell- dependent adaptive immune responses, in part, by ubiquitinating and causing the subsequent degradation of Cbl-b. The experimental focus of this research is to delineate pathways regulated by Nedd4 in the T cell and characterize their impact on the immune response. We will accomplish this in the following ways. First, we will determine how Nedd4 regulates Cbl-b to promote T cell activation. We hypothesize that following T cell activation, Nedd4 becomes activated and initiates degradation of Cbl-b, thus lengthening the duration of T cell activation. To test this, we will measure the half-life of Cbl-b in resting and stimulated T cells and determine whether degradation of Cbl-b occurs via the lysosome or the proteasome. We will then determine where in the cell Nedd4 and Cbl-b interact. Finally, we will determine whether the increased levels of Cbl-b in Nedd4-1-/- T cells are responsible for the decreased proliferation and IL-2 production observed in these cells. Second, we will define the functional repertoire of Nedd4 in immune function. Nedd4-/-FLCh mice do not mount an effective immune response. This could be because of an intrinsic defect in the T cell or it could be due, in part, to a defect in antigen presenting cells. Thus, we will test the extent of the T cell defect in these mice. We will determine whether the observed defects are T cell-intrinsic or exacerbated by defects in Nedd4-/- antigen presenting cells. Finally, we will study the role of Nedd4 in the adaptive immune response. To study whether Nedd4 is required for cell-mediated immune responses, we will use the Lymphocytic Choriomeningitis Virus (LCMV) infection model. The test whether Nedd4 is required for humoral immune responses, we induce autoimmune disease using the collagen induced arthritis model. Our long-term goal is to study how ubiquitination pathways regulated by Nedd4 regulate T cell activation and adaptive immunity. We believe that Nedd4-dependent pathways could be targeted therapeutically to treat immune-mediated diseases such as autoimmune disease.

Public Health Relevance

We propose to study the function of enzymes that regulate protein removal from T cells. These enzymes promote T cell function and thus impact many immune mediated events. These studies have the potential to identify novel therapeutic targets for regulating the immune response, and might provide new treatments options to clinically manage autoimmune and inflammatory diseases.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
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Mallia, Conrad M
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Children's Hospital of Philadelphia
United States
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Mei, Junjie; Liu, Yuhong; Dai, Ning et al. (2012) Cxcr2 and Cxcl5 regulate the IL-17/G-CSF axis and neutrophil homeostasis in mice. J Clin Invest 122:974-86