The Nucleotide-binding domain, leucine-rich repeat family is comprised of 22 genes. Among this family, the CIITA (class II transactivator) is the founding member. CIITA is the master transcriptional activator regulator of both classical and nonclassical (DM and DOa) MHC-ll genes. In addition to MHC-II, we identified Plexin Al (Plxnal) as a novel gene that is also regulated by CIITA in dendritic cells. The Plexin molecules 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. During the last three and a half years, a large component of our effort was focused on the initial aims which are largely accomplished as follows: (1) We found that the Plxnal gene has two promoters, one of which is regulated by CIITA, other transcription factors and by histone modifying enzymes;by contrast, a promoter that is more preferentially utilized in neuronal cells is not regulated by CIITA;(2) we showed that Plexin A l affects the Rho GTPase pathway to alter actin polarization in dendritic cells;and (3) we showed that Sema6p on T cells and PIxnAI on DC represent a pair of ligand-receptor, and the T cell signaling pathway that is activated upon Sema6D engagement is conducted via the c-abl/CrL pathway. In addition to what we proposed, we significantly expanded the scope to identify other immune plexin family members and their functional and molecular role in the immune system. We identified and revealed three plexins and their immune functions: (1) Plexin-A4 is a surface molecule expressed by macrophages and dendritic cells that is required for optimal signaling through TLR to cause Rac GTPase activation;(2) Plexin-B2 is expressed by macrophages and is important for cell motility by regulating Rac and Cdc42 activation;and (3) Plexin-DI is expressed by lymphocytes and regulates germinal B cell migration and development. In addition, we also expanded our analysis to the transcriptional regulation of NLRs, including CIITA and NLRP12 and found that both are inhibited by the Blimp-1 factor. In the new proposal, we plan to examine the role of plexins in inflammatory disorders, and to study the regulation of NLR gene transcription.

Public Health Relevance

The Nucleotide-binding domain, leucine-rich repeat containing family (NLR) has gained much attention due to their effects on adaptive and innate immunity. One ofthe founding members, CIITA, induces the transcription of Plexin-AI. This work will focus on the disease-relevance of plexins, on the transcriptional regulation of NLRs, and on the interactome that contains NLR to influence gene transcription that can affect immunologic outcome and diseases.

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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Special Emphasis Panel (NSS)
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Gondre-Lewis, Timothy A
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University of North Carolina Chapel Hill
Schools of Medicine
Chapel Hill
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