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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Palker, Thomas J
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Yale University
Schools of Medicine
New Haven
United States
Zip Code
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
Palm, Noah W; Medzhitov, Ruslan (2013) Role of the inflammasome in defense against venoms. Proc Natl Acad Sci U S A 110:1809-14
Jamieson, Amanda M; Pasman, Lesley; Yu, Shuang et al. (2013) Role of tissue protection in lethal respiratory viral-bacterial coinfection. Science 340:1230-4
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
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
Medzhitov, Ruslan; Schneider, David S; Soares, Miguel P (2012) Disease tolerance as a defense strategy. Science 335:936-41
Kotas, Maya E; Lee, Hui-Young; Gillum, Matthew P et al. (2011) Impact of CD1d deficiency on metabolism. PLoS One 6:e25478
Nish, Simone; Medzhitov, Ruslan (2011) Host defense pathways: role of redundancy and compensation in infectious disease phenotypes. Immunity 34:629-36

Showing the most recent 10 out of 20 publications