CIITA (class II transactivator) is the master transcriptional activator regulator of both classical and nonclassical (DM and DOa) MHC-II genes. Mutations within this gene form the genetic basis for the immunodeficiency, type II group A Bare Lymphocyte Syndrome (BLS). CIITA functions by interacting with transcription factors that directly bind the MHC-II promoter such as RFX/CREB and NF-Y. CIITA is an early step of promoter loading, and is required for subsequent epigenetic changes including the recruitment of histone acetylases and methylases to MHC-II promoters. In addition to MHC-II, we recently identified Plexin A1 (Plxna1) as a novel gene that is also regulated by CIITA. This was accomplished by profiling cDNA isolated from primary dendritic cells (DC) obtained from CIITA-deficient mice versus wildtype mice. Plexins comprise a large gene family and are considered the receptor for semaphorin family members. They were initially identified in neurons as important for neuronal guidance and axonal growth and serve as either retractive or attractive signals to guide axonal extension. We use short-hairpin RNA (shRNA) to block Plxna1 in DCs and show that Plxna1 is important for antigen-specific T cell stimulation. Plxna1 shRNA blocks the ability of DCs to stimulate T cells by >80%. Plxna1 is not involved in peptide processing or antigenic-peptide binding. Preliminary data suggest it functions in Rho but not cdc42 or Rac activation, and is important in actin polarization. Additional data suggest that Semaphorin 6D (Sema6D) is a candidate T cell ligand for Plxna1 on DC. We elect to study three major aspects of the Plxna1 and Sema6D pair in primary DC and T cells: (1) The transcriptional regulation of Plxna1 by CIITA, by other transcription factors and by histone modifying enzymes;(2) the functional effects of Plxna1 on the Rho GTPase pathway;and (3) the interaction of Sema6D on T cells and PlxnA1 on DC, and the T cell signaling pathway that is activated upon Sema6D engagement.
This project focuses on two new molecules, Plexin-A1 and Semaphorin 6D, that control T lymphocyte activation. Plexin-A1 and Semaphorin 6D are important for the optimal activation of T cells by dendritic cells. T lymphocyte activation is central in immunology, and is important in autoimmunity, infectious diseases, vaccine development among other clinically-relevant issues.
|Huang, Juin-Hua; Liu, Chu-Yu; Wu, Sheng-Yang et al. (2018) NLRX1 Facilitates Histoplasma capsulatum-Induced LC3-Associated Phagocytosis for Cytokine Production in Macrophages. Front Immunol 9:2761|
|Swanson, Karen V; Junkins, Robert D; Kurkjian, Cathryn J et al. (2017) A noncanonical function of cGAMP in inflammasome priming and activation. J Exp Med 214:3611-3626|
|Freeman, Leslie; Guo, Haitao; David, Clément N et al. (2017) NLR members NLRC4 and NLRP3 mediate sterile inflammasome activation in microglia and astrocytes. J Exp Med 214:1351-1370|
|Zhang, Song; Takaku, Motoki; Zou, Liyun et al. (2017) Reversing SKI-SMAD4-mediated suppression is essential for TH17 cell differentiation. Nature 551:105-109|
|Rotty, Jeremy D; Brighton, Hailey E; Craig, Stephanie L et al. (2017) Arp2/3 Complex Is Required for Macrophage Integrin Functions but Is Dispensable for FcR Phagocytosis and In Vivo Motility. Dev Cell 42:498-513.e6|
|Bruce, Danny W; Stefanski, Heather E; Vincent, Benjamin G et al. (2017) Type 2 innate lymphoid cells treat and prevent acute gastrointestinal graft-versus-host disease. J Clin Invest 127:1813-1825|
|Chen, Liang; Wilson, Justin E; Koenigsknecht, Mark J et al. (2017) NLRP12 attenuates colon inflammation by maintaining colonic microbial diversity and promoting protective commensal bacterial growth. Nat Immunol 18:541-551|
|Snouwaert, John N; Nguyen, MyTrang; Repenning, Peter W et al. (2016) An NLRP3 Mutation Causes Arthropathy and Osteoporosis in Humanized Mice. Cell Rep 17:3077-3088|
|Guo, Haitao; König, Renate; Deng, Meng et al. (2016) NLRX1 Sequesters STING to Negatively Regulate the Interferon Response, Thereby Facilitating the Replication of HIV-1 and DNA Viruses. Cell Host Microbe 19:515-528|
|Koblansky, A Alicia; Truax, Agnieszka D; Liu, Rongrong et al. (2016) The Innate Immune Receptor NLRX1 Functions as a Tumor Suppressor by Reducing Colon Tumorigenesis and Key Tumor-Promoting Signals. Cell Rep 14:2562-75|
Showing the most recent 10 out of 37 publications