Toll-like receptors (TLRs) function as critical sensors of microbial infection. Upon recognition of microbial ligands, TLRs induce innate immune responses that are critical for host resistance against many types of microbial infections. In addition, TLRs induce dendritic cell maturation and activation of adaptive immune responses. We have previously characterized several aspects of TLR-mediated control of adaptive immunity. In the current application, we propose to investigate the cell type specific functions of TLRs and the IL-1 family receptors in vivo using conditional deletion of MyD88 in several cell types. We will investigate the role of TLR signaling in various cell types in innate resistance to infection and in the induction of adaptive immune responses. We will examine in detail TLR-dependent and TLR-independent mechanisms of B cell activation for antibody production. We will investigate the mechanisms whereby TLR induced signals block the induction of peripheral T cell tolerance, and the functional and mechanistic connection between these signals and suppression of T cell responses by regulatory T cells. Specifically, we will characterize the role of IL-6 signaling in T cells in the regulation of T cell activation and differentiation and suppression by regulatory T cells.
Infectious and inflammatory diseases and autoimmunity carry a significant burden on public health. In this proposal we will investigate basic mechanisms that are involved in organism's protection from infections and mechanisms that prevent the development of autoimmune diseases.
|Okin, Daniel; Medzhitov, Ruslan (2016) The Effect of Sustained Inflammation on Hepatic Mevalonate Pathway Results in Hyperglycemia. Cell 165:343-56|
|Schenten, Dominik; Nish, Simone A; Yu, Shuang et al. (2014) Signaling through the adaptor molecule MyD88 in CD4+ T cells is required to overcome suppression by regulatory T cells. Immunity 40:78-90|
|Bezbradica, Jelena S; Rosenstein, Rachel K; DeMarco, Richard A et al. (2014) A role for the ITAM signaling module in specifying cytokine-receptor functions. Nat Immunol 15:333-42|
|Chang, Pamela V; Hao, Liming; Offermanns, Stefan et al. (2014) The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition. Proc Natl Acad Sci U S A 111:2247-52|
|Nish, Simone A; Schenten, Dominik; Wunderlich, F Thomas et al. (2014) T cell-intrinsic role of IL-6 signaling in primary and memory responses. Elife 3:e01949|
|Palm, Noah W; Medzhitov, Ruslan (2013) Role of the inflammasome in defense against venoms. Proc Natl Acad Sci U S A 110:1809-14|
|Kotas, Maya E; Jurczak, Michael J; Annicelli, Charles et al. (2013) Role of caspase-1 in regulation of triglyceride metabolism. Proc Natl Acad Sci U S A 110:4810-5|
|Palm, Noah W; Rosenstein, Rachel K; Yu, Shuang et al. (2013) Bee venom phospholipase A2 induces a primary type 2 response that is dependent on the receptor ST2 and confers protective immunity. Immunity 39:976-85|
|Jamieson, Amanda M; Pasman, Lesley; Yu, Shuang et al. (2013) Role of tissue protection in lethal respiratory viral-bacterial coinfection. Science 340:1230-4|
|Gao, Yan; Nish, Simone A; Jiang, Ruoyi et al. (2013) Control of T helper 2 responses by transcription factor IRF4-dependent dendritic cells. Immunity 39:722-32|
Showing the most recent 10 out of 29 publications