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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Method to Extend Research in Time (MERIT) Award (R37)
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Cellular and Molecular Immunology - B Study Section (CMIB)
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Gondre-Lewis, Timothy A
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University of North Carolina Chapel Hill
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Chapel Hill
United States
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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
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 19:515-28
Freeman, Leslie C; Ting, Jenny P-Y (2016) The pathogenic role of the inflammasome in neurodegenerative diseases. J Neurochem 136 Suppl 1:29-38
Kang, Min-Jong; Yoon, Chang Min; Kim, Bo Hye et al. (2015) Suppression of NLRX1 in chronic obstructive pulmonary disease. J Clin Invest 125:2458-62
Koehn, Brent H; Apostolova, Petya; Haverkamp, Jessica M et al. (2015) GVHD-associated, inflammasome-mediated loss of function in adoptively transferred myeloid-derived suppressor cells. Blood 126:1621-8
Wilson, Justin E; Petrucelli, Alex S; Chen, Liang et al. (2015) Inflammasome-independent role of AIM2 in suppressing colon tumorigenesis via DNA-PK and Akt. Nat Med 21:906-13
Guo, Haitao; Callaway, Justin B; Ting, Jenny P-Y (2015) Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat Med 21:677-87
Aachoui, Youssef; Kajiwara, Yuji; Leaf, Irina A et al. (2015) Canonical Inflammasomes Drive IFN-γ to Prime Caspase-11 in Defense against a Cytosol-Invasive Bacterium. Cell Host Microbe 18:320-32
Krauss, Jennifer L; Zeng, Rong; Hickman-Brecks, Cynthia L et al. (2015) NLRP12 provides a critical checkpoint for osteoclast differentiation. Proc Natl Acad Sci U S A 112:10455-60
Rodgers, Mary A; Bowman, James W; Fujita, Hiroaki et al. (2014) The linear ubiquitin assembly complex (LUBAC) is essential for NLRP3 inflammasome activation. J Exp Med 211:1333-47

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