Browsing by Author "Ryan, Jennifer Carrie"

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    MECHANISMS OF TGF BETA-INDUCED INHIBITION OF CD1D-MEDIATED ANTIGEN PRESENTATION
    (2011-11-18) Ryan, Jennifer Carrie; Brutkiewicz, Randy R.; Bauer, Margaret E.; Blum, Janice Sherry, 1957-; Dunn, Kenneth William; Quilliam, Lawrence
    CD1d is a cell surface glycolipid that, like Major Histocompatibility Complex (MHC) class I and MHC class II molecules, presents antigen. However, instead of peptides, CD1d presents lipids to Natural Killer (NK) T cells, a subset of T cells that express both NK cell markers and the T cell receptor and produces both T helper (Th) 1 and Th2 cytokines. Our lab focuses on the regulation CD1d-mediated antigen presentation. TGF beta is a known regulator of the immune system, such as controlling MHC class II antigen presentation. Further, TGF beta can activate the mitogen activated protein kinase (MAPK) p38, a known negative regulator of CD1d-mediated antigen presentation. Therefore, we hypothesized that TGF beta would be a negative regulator of CD1d-mediated antigen presentation, and our results showed a decrease in antigen presentation by CD1d in response to TGF beta treatment. However, this inhibition was not through p38 activation, as indicated by the absence of a rescue of CD1d-mediated antigen presentation in, TGF beta-treated, p38 dominant negative-expressing cells. Alternatively, the Smad pathway, the canonical pathway activated by TGF beta, was investigated through a lentivirus shRNA-mediated knockdown of Smad2, Smad3 and Smad4 proteins. Smad2 shRNA-expressing cells showed in an increase in CD1d-mediated antigen presentation, suggesting an inhibitory role for Smad2. In contrast, Smad3 shRNA-expressing cells did not differ from control cells. However, as in the case of Smad2, CD1d+ cells in which Smad4 was knocked down, were substantially better at CD1d-mediated antigen presentation than control cells, suggesting that it also negatively regulates antigen presentation. Overall, these studies demonstrate that the canonical TGF beta/Smad pathway regulates an important part of the host’s innate immune response, vis-à-vis CD1d-mediated antigen presentation.