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Differentiation from stem cells into mature cells of any tissue requires the concerted efforts of transcription factors, which activate necessary gene expression programs, and epigenetic mechanisms, which lock in these programs. To understand these basic mechanisms, we study the signaling pathways and transcriptional networks involved in development of T lymphocytes and in their responses to inflammatory microbial signals.
The majority of mature T lymphocytes fall into one of two functional categories: helper cells, which react with peptides complexed to major histocompatibility complex (MHC) class II molecules on antigen-presenting cells, and cytotoxic cells, which recognize peptides bound to MHC class I molecules. These cells are distinguished on the basis of surface expression of the CD4 or CD8 coreceptors, which are coexpressed on immature double-positive (DP) thymocytes but are singly expressed upon maturation on thymocytes with T cell antigen receptors (TCRs) specific for class II and class I, respectively.
As commitment to the cytotoxic or helper lineage is coupled to the transcriptional shutoff of cd4 or cd8, we have studied the transcriptional regulation of the coreceptor genes to understand the mechanism of lineage specification. We identified a region within the Cd4 gene that is required to initiate, but not maintain the silencing of cd4 expression in the cytotoxic T cell lineage. Further, we have shown that an enhancer necessary to initiate cd4 expression in DP thymocytes, establishes a heritable state of active gene expression that is maintained in mature T helper cells even after the enhancer’s deletion. Thus, Cd4 is regulated by heritable ON and OFF epigenetic mechanisms. Work to identify trans-acting factors involved in the initiation and maintenance of these heritable states has yielded the Runx 1 and 3 transcription factors, which are crucial for the differentiation of helper and cytotoxic T cells, respectively. In addition, we have shown that the transcription factor ThPOK, which is required for helper T cell differentiation, represses Runx3 and thus, cytotoxic T cell fate. We continue to seek to identify the transacting factors that participate in the transcriptional network critical to coreceptor expression and lineage choice. Currently we are especially interested in the role of DNA methylation and noncoding RNAs in lineage specification and cd4 silencing.
Naïve helper T cells can differentiate into different flavors of effector helper cells, which are defined by cytokine secretion patterns and are critical for defense against certain types of infections. A proinflammatory subset, called Th17 cells, expresses the cytokines interleukin-17 (IL-17) and IL-22, and is especially important for immunity to extracellular pathogens, particularly at mucosal sites. In addition, aberrant activation of these cells is thought to be involved in a wide range of autoimmune diseases, including multiple sclerosis, arthritis and inflammatory bowel disease. Our work has shown that the transcription factor RORgt is a central regulator of Th17 cells: forced expression of RORgt induces IL-17, while its deletion largely abrogates IL-17 expression and pathogenesis associated with mouse models of multiple sclerosis. We have shown that signals from TGF-b, IL-6, IL-21 and IL-23 synergize to induce RORgt expression and program Th17 differentiation. Further we have identified a commensal gut microbe, Segmented Filamentous Bacteria, whose presence induces Th17 cell differentiation.
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bioRxiv : the preprint server for biology (2023)
user-5d8054e8530c708f9920ccce(2019)
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The Journal of Immunologyno. 1_Supplement (2016): 199.3-199.3
Inflammation Research (2014)
openalex(2014)
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Jacques Ravel,Martin J. Blaser,Jonathan Braun,Eric Brown,Frederic D. Bushman,Eugene B. Chang,Julian Davies,Kathryn G. Dewey,Timothy Dinan,Maria Dominguez-Bello,Susan E. Erdman,B. Brett Finlay,Wendy S. Garrett,Gary B. Huffnagle,Curtis Huttenhower,Janet Jansson,Ian B. Jeffery,Christian Jobin,Alexander Khoruts,Heidi H. Kong,Johanna W. Lampe,Ruth E. Ley,Dan R. Littman,Sarkis K. Mazmanian,David A. Mills,Andrew S. Neish,Elaine Petrof,David A. Relman,Rosamond Rhodes,Peter J. Turnbaugh,Vincent B. Young,Rob Knight, Owen White
user-5f8411ab4c775e9685ff56d3(2014)
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semanticscholar(2013)
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#Papers: 23
#Citation: 1144
H-Index: 7
G-Index: 23
Sociability: 5
Diversity: 0
Activity: 0
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