Jenny P. Y. Ting, Ph.D.

jenny_ting@med.unc.edu 22-004 Lineberger Comprehensive Cancer Center Campus Box 7295 Chapel Hill, NC 27599-7295 919.966.5538

Research

Co-Director, Inflammatory Diseases Institute
Director, Center for Translational Immunology
Program Leader, Lineberger Comprehensive Cancer Center
UCRF Program Planning Committee
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Our laboratory has broad interest in the application of cutting edge ideas and technology to the study of disease-relevant issues. Major directions include innate immunity, dendritic cell function, oxidative-stress, apoptosis, signal transduction, gene discovery, functional genomics and proteomics, gene regulation, molecular immunology, neuro-inflammation and microglial cells. Clinical issues of interest include multiple sclerosis, cancer, transplantation, infection and inflammation.

These divergent studies are incorporated into four major directions relying heavily on transcriptosome profiling, 2D gel-mass spectroscopy and proteome analysis, gene-ablation in mice and RNA interference. These new approaches are integrated with traditional approaches employed to study signal transduction, transcription, protein-interaction and modification, coupled with biologic studies to understand innate and adaptive immunity in diseases. Trainees typically are exposed to an enormous repertoire of expertise and approaches, and they are highly competitive after graduation.

CIITA and the plexin-A1 gene
We have studied the transcriptional master regulator of Major Histocompatibility (MHC) genes called CIITA (class II transactivator) for over a decade. CIITA is extremely important as patients with defects in the gene exhibit severe immunodeficiency. It has even broader clinical importance as polymorphism (SNP) in the CIITA has been linked to multiple sclerosis, arthritis and heart disease (the latter has a strong inflammatory component). CIITA promotes the recruitment of DNA-binding protein, transcription cofactors, and histone acetylases/methylases to the promoter as determined by in vivo footprinting and chromatin immunoprecipitation. More recently we found that CIITA also activates the plexin-A1 gene in dendritic cells. Plexin-A1 has not been previously reported in the immune system, and is typically thought to be important for neuronal interaction and retraction. Plexins typically interact with semaphorins either on the cell membrane or upon secretion. Our new finding presents a completely new framework to think about how immune cells attract and repulse each other. We are pursuing the following directions: (1) A significant effort is devoted to understanding how CIITA transcriptionally activates plexin-A1 expression in dendritic cells (2) We show that plexin-A1 controls Rho GTPase activation, actin polarization and antigen presentation; we want to understand how plexin affects these different processes. (3) Other plexin molecules are differentially expressed by distinct immune cell subpopulations. We are trying to understand their roles in immunity.

Ting JP, Trowsdale J. Genetic control of MHC class II expression.
Cell. 2002, 109 Suppl:S21-3

Wong AW et al., CIITA-regulated plexin-A1 affects T-cell-dendritic cell interactions. Nat Immunol. 2003, 4(9):891-8

:Zika E, Fauquier L, Vandel L, Ting JP. Interplay among coactivator-associated arginine methyltransferase 1, CBP, and CIITA in IFN-gamma-inducible MHC-II gene expression. Proc Natl Acad Sci U S A. 2005 Nov 8;102(45):16321-6.


CATERPILLER (CLR) or NOD-LRR genes: A Family of New Inflammatory and Apoptotic Genes
Based on the structure of CIITA, we have found a large family of genes that encode similar structural motifs as CIITA, which we have termed the CATERPILLER gene family. These mammalian genes are conserved all through plants (R genes). In plants, R genes are important for immune defense against bacteria, viruses, fungi, parasites and even insecticides. It is anticipated that mammalian CLRs have a similar function. In support of this, several human CLR genes are the primary genetic causes of immunologic disorders, including immunodeficiency, Inflammatory Bowel Disease, and periodic auto-inflammation. Our studies show that these genes are crucial in the control of inflammatory, anti-inflammatory and apoptotic responses in mammals. They can reduce or amplify signaling pathways mediated by the Toll-like receptor (TLR) family, TNF receptor family, IL-1 receptor, NF-?B, and AP-1. RNA interference, gene ablation, genomics, yeast two-hybrid, biochemical and proteomics analyses are performed to understand the functions of these novel genes. In addition to understanding their role in the control of inflammation, another focus is on the role of CLRs in apoptosis. CLR proteins are similar in structure to an apoptotic inducer, Apaf-1. We find that mutant CLR associated with disease causes increased apoptosis. Thus CLR proteins affect both inflammatory and apoptotic processes. This project involves understanding how CLR affects cell signaling (such as in the TLR, TNF, IL-1, NF-kB, AP-1 and MAPK pathways), apotosis (such as caspase activation and apoptosome formation), and elucidating the biological role of these proteins in infection, inflammation and autoimmunity.
In addition to the studies described above, significant research is devoted to understanding how CLR genes affect innate and adaptive immunity, particularly during infections. Infectious models include M. tuberculosis, F. tularenesis (a bioterrorism agent), P. gingivalis (an oral/dental pathogen) and various viral models. .


Ting JP, Davis BK. CATERPILLER: a novel gene family important in immunity, cell death, and diseases. Annu Rev Immunol. 2005;23:387-414.

Conti BJ et al., CATERPILLER 16.2 (CLR16.2), a novel NBD/LRR family member that negatively regulates T cell function. J Biol Chem. 2005; 280(18):18375-85

Williams KL, Lich JD, Duncan JA, Reed W, Rallabhandi P, Moore C, Kurtz S, Coffield VM, Accavitti-Loper MA, Su L, Vogel SN, Braunstein M, Ting JP. The CATERPILLER protein monarch-1 is an antagonist of toll-like receptor-, tumor necrosis factor alpha-, and Mycobacterium tuberculosis-induced pro-inflammatory signals. J Biol Chem. 2005, 280(48):39914-24.

Ting JP, Kastner DL and Hoffman HM. CATERPILLERs, pyrin, and hereditary immunologic disorders. Nature Reviews Immunology March 2006

The Detrimental and Beneficial Roles of CNS Inflammation in Disease Progression and Resolution –
Inflammation occurs in a number of neurologic diseases such as Alzheimer's, Parkinson's, Huntington's and multiple sclerosis (MS). Inflammation in the CNS includes the induction of interleukins, complement, tumor necrosis factors, nitric oxide, class I and II MHC antigens. To examine the role of neuroinflammatory during disease progression and resolution, we have used a disease model where demyelination and remyelination can be predictably induced by feeding or withdrawing a neurotoxicant in the diet. Using mice with mutations in inflammatory genes, we found that many of these genes are not only crucial in disease progression (demyelination), but also in disease resolution (remyelination). This is unexpected and clearly demonstrates that not all inflammatory responses are bad. In specific we found that while TNF plays a minor role during demyelination, it is crucial for normal remyelination to occur. In contrast, a TNF-related gene, lymphotoxin worsens demyelination, but has little effect on the repair process. Hence we suggest that blocking lymphotoxin may be beneficial to MS patients. Preliminary data indicate that this may be the case. A global view was provided with a cDNA microarray analysis of over 10,000 genes. Our results show wide-ranging changes in inflammatory genes, but also transcription factors, new apoptotic genes, and differentiation factors. Current research is focused on understanding how these genes affect demyelination and remyelination, how the TNF family affects repair versus damage, and whether the TNF pathway provides therapeutic intervention for CNS diseases. Translational research is ongoing to test biologics or small molecules for their roles in reducing neuroinflammation and demyelination, while enhancing remyelination. Experiments are also ongoing to decipher what can cause oligodendrocyte precursor or stem cells to undergo reparative growth.

Arnett HA et al., TNF alpha promotes proliferation of oligodendrocyte progenitors and remyelination. Nat Neurosci. 2001, (11):1116-22

Plant SR, Arnett HA, Ting JP. Astroglial-derived lymphotoxin-alpha exacerbates inflammation and demyelination, but not remyelination. Glia. 2005, 49(1):1-14

New Biomarkers and the Importance of Oxidative Stress in Cancer
Biomarkers for cancer will play an increasingly important role for the diagnosis, prognosis and treatment of patients. We searched for biomarkers that accompany successful chemotherapy by proteomic array analysis, and found a novel marker. Increased DJ-1 expression is associated with lung, breast and ovarian cancers. DJ-1 has central role in stabilizing anti-oxidative stress in lung tumors. This is achieved by stabilizing transcription factors in the anti-oxidative pathways. This is highly relevant because lung tissues are constantly exposed to oxidative stress. DJ-1 expression is heightened in lung cancers to protect the cancers from oxidative stress. Intriguingly, DJ-1 is mutated in Parkinson’s patients, and causes increased neuronal cell death. We hypothesize that DJ-1 normally protects cells from oxidiative stress. In cancer, elevated DJ-1 protects cancer cells, while the Parkinson mutation results in a defective protein and reduced neuronal survival. This project relies on RNA interferences and DJ-1 defective mice to understand the in vitro and in vivo function of DJ-1. Our studies have now revealed the molecular mechanism bywhich this important protein mediates its anti-oxidative stress functions. In addition, experiments are ongoing to assess the validity of DJ-1 as a cancer prognostic or diagnostic biomarker.

MacKeigan et al., Proteomic profiling drug-induced apoptosis in non-small cell lung carcinoma: identification of RS/DJ-1 and RhoGDIalpha. Cancer Res. 2003

Publications

Felix N, Brickey WJ, Griffiths R, VanKaer L, Coffman T and Ting JP. H2-Ma-
mice show the importance of allogeneic peptide in cardiac allograft rejection. J. Exp. Med., 192(1):31-40, 2000.

Zhu X-S, Linhoff MW, Guoxuan L, Chin K-C, Ting JP. A transcriptional scaffold: CIITA interacts with NF-Y, RFX and CREB to cause stereospecific regulation of the class II MHC promoter. Mol. Cell Biol. 20(16):6051-6061, 2000.

Harton JA, Ting JP. Class II transctivator (CIITA): mastering the art of MHC expression. Mol. Cell. Biol. 20(17):6185-94, 2000.

Piskurich JF, Lin K-I, Lin Y, Wang Y, Ting JP, Calame K. Blimp-1/PRDI-BF1 mediates extinction of Major Histocompatibility Class I Transactivator (CIITA) expression in plasma cells. Nature Immunology, 1(6); 526-532, 2000.

Chatterjee-Kishore M, Wright KL, Ting JP, Stark GR. How Stat1 mediates constitutive gene expression: A complex of unphosphorylated Stat1 and IRF1 supports transcription of the LMP2 gene. EMBO J. 19(15):4111-4122, 2000.

Aparna R, Howcroft TK, Weissman JD, Kirshner S, Zheng X, Yokoyama K, Ting JP and Singer DS. Transcriptional co-activator, CIITA, is an acetyl transferase that bypasses a promoter requirement for TAFII250. Molecular Cell. 7:105-115, 2001.

Linhoff M, Ting JP. Two Distinct Domains within CIITA Mediate Self-Association: Involvement of the GTP-Binding and Leucine-Rich Repeat Domains. Mol. Cell Biol 21(9):3001-11, 2001.

Li, G, Harton, JP, Zhu, XS, and Ting, JP. Downregulation of CIITA function by PKA-mediated phosphorylation: Mechanisms of PGE/cAMP/PKA inhibition of class II MHC expression in monocytic lines. Mol. Cell. Biol. 21: 4626-4635, 2001.

Morrison, TE, Mauser A, Wong, A, Ting JP, and Kenney SC. Inhibition of IFN signaling by an Epstein-Barr virus immediate-early protein. Immunity. 15(5):787-99, 2001.

Arnett, HA, Mason, J., Marino, M, Suzuki, K, Matsushima,GK, and Ting, JP. TNFa signaling through TNFR2 promotes proliferation of oligodendrocyte progenitors and remyelination. Nature Neuroscience. 4(11):1116-22, 2001.

Ting JP, Trowsdale J. Genetic Control of MHC Class II Expression. Cell. Vol 109. S21-33, 2002.

Harton JA, Linhoff MW, Zhang J, Ting JP. CATERPILLER: A large family of mammalian genes containing CARD, Pyrin, NBD, and LRR domains. J Immunol. 169(8):4088-93, 2002.

Williams KL, Taxman DJ, Linhoff MW, Reed W and Ting JP. Monarch-1: A Pyrin/NBD/LRR protein that controls classical and non-classical MHC-I genes. J. Immunol. Cutting Edge, 170:5354, 2003.

Wong AW, Brickey WJ, Taxman DJ, van Deventer HW, Reed W, Gao JX, Zheng P, Liu Y, Li P, Blum JS, McKinnon KP, Ting JP. Plexin-A1: a target of CIITA in dendritic cells and importance in T cell-dendritic cell interactions. Nature Immunol. 4:891, 2003.

Greer SF, Zika E and Ting JP. Enhancement of CIITA transcriptional function by ubiquitin. Nat Immunol. 4:1074, 2003.

MacKeigan JP, Clements C, Pope M, Lich J, and Ting JP. Proteomic profiling drug-induced apoptosis in non-small cell lung carcinoma: identification of RS/DJ-1 and RhoGDIalpha. Cancer Res. 63:6928, 2003.

Arnett HA, Wang Y, Matsushima GK, Suzuki K, Ting JP. Functional genomic analysis of remyelination reveals importance of inflammation in oligodendrocyte regeneration. J Neurosci. 23:9824, 2003.

Serine residues 286, 288, and 293 within the CIITA: a mechanism for down-regulating CIITA activity through phosphorylation. J Immunol. 173(1):376-83, 2004.

Plant SR, Arnett HA, Ting JP. Astroglial-derived lymphotoxin-alpha exacerbates inflammation and demyelination, but not remyelination. Glia. 49(1):1-14, 2005.

Ting JP and Davis B. CATERPILLER: A novel gene family important in immunity, cell death and diseases. Annu Rev Immuno. 23:387-414, 2005.

Zika E and Ting JP. Epigenetic control of MHC-II: Interplay between CIITA and histone modifying Enzymes. Current Opinion in Immunology, 17(1):58-64, 2005.

Conti BJ, Davis BK, Zhang J, O'Connor W, Williams KL, and Ting JP. Caterpiller 16.2 (CLR16.2): A novel NBD/LRR family member that negatively regulates T cell function. J. Biol. Chem. 280:18375-18385; 2005.

Williams KL, Lich JD, Rallabhandi P, Reed W, Kurtz S, Coffield VM, Su L, Vogel SN, Braunstein M and Ting JP. Monarch-1 is an Antagonist of TLR-induced Pro-inflammatory Signal Transduction. J. Biol. Chem. 280:39914-24, 2005.

Zika E, Fauquier L, Vandel L, Ting JP. Interplay among coactivator-associated arginine methyltransferase 1, CBP, and CIITA in IFN-{gamma}-inducible MHC-II gene expression. Proc Natl Acad Sci. 102(45):16321-6, 2005.

Plant SR, Wang Y., Vasseur S., Thrash JC, McMahon E, Arnett, HA, Miller S, Carson, MJ, Iovanna JL, and Ting JP. Upregulation of the stress-associated gene p8 in mouse models of demyelination and in multiple sclerosis tissues. Glia. 53(5):529-37, 2006.

Ting JP, Hoffman HA, Kastner D. CATERPILLER genes and periodic fever syndromes. Nature Rev. Immunol. March 6(3):183-95, 2006.

Hoffman BG, Williams KL, Tien AH, Lu V, de Algara TR, Ting JP, Helgason CD. Identification of novel genes and transcription factors involved in spleen, thymus and immunological development and function. Genes and Immunity. 7(2):101-12, 2006.

Taxman DJ, Livingstone LR, Zhang J, Conti BJ, Iocca HA, Williams KL, Lich JD, Ting JP, Reed W. Criteria for effective design, construction, and gene knockdown by shRNA vectors. BMC Biotechnol. 24(6):7, 2006.

Lich JD, Arthur JA, Ting JP. Cryopyrin: in from the cold. Immunity. 24(3):241-3, 2006.

Bergstralh DT, Ting JP. Microtubule stabilizing agents: Their molecular signaling consequences and the potential for enhancement by drug combination. Cancer Treat Rev. 32(3):166-79. 2006.

Eun Y, O’Connor BP, Wong AW, van Deventer H, Taxman DJ, Reed W, Li P, Blum JS, McKinnon KP, Ting JP. Rho activation and actin polarization are dependent on plexin-A1 in dendritic cells. J. Immunol. Cutting Edge, Oct 177(7):4271-5, 2006.

Clements CM, McNally RS, Conti BJ, Mak TW, Ting JP. DJ-1/PARK 7 stabilizes the anti-oxidant transcriptional master regulator, Nrf2: Implications in cancer and Parkinson’s disease. Proc. Natl. Acad. Science, 103(41):15091-6, 2006.

Taxman DJ, Zhang J, Champagne C, Bergstralh DT, Iocca HA, Lich JD, Ting JP. ASC mediates the induction of multiple cytokines by Porphyromonas gingivalis via caspase 1-dependent and independent pathways. J. Immunol. Cutting Edge, 177(7):4252-6, 2006.

Lich JD, Williams KL, Moore CB, Arthur JC, Davis BK, Taxman DJ, Ting JP. Cutting Edge: Monarch-1 Suppresses Non-Canonical NF-kappaB Activation and p52-Dependent Chemokine Expression in Monocytes. J Immunol., Cutting Edge. 178(3):1256-60, 2007.

Bergstralh DT, Conti BJ, Moore CB, Brickey WJ , Taxman DJ , and Ting JP. Global functional analysis of nucleophosmin in Taxol response, cancer, chromatin regulation, and ribosomal DNA transcription. Exp Cell Res. 313:65-76, 2007.

Duncan JA, Bergstralh DT, Wang Y, Willingham SB, Ye Z, Zimmermann AG, Ting JP. Cryopyrin/NALP3 binds ATP/dATP, is an ATPase, and requires ATP binding to mediate inflammatory signaling. Proc. Natl. Acad. Science 104: 8041-6, 2007.

Duncan JA and Ting JP. Rebuilding Host-Pathogen Interaction from the Ground Up: In Vitro Reconstitution of the Inflammasome Cell, Host and Microbes. 1:7-9, 2007.

Click here for a list of publications

Accomplishments

Outstanding Research into the Cause and Cure of Multiple Sclerosis
National Multiple Sclerosis Society, 2001

Teaching Excellence Award
University of North Carolina at Chapel Hill, 2002

Award for Outstanding Contribution to the field of Immunology and Immunity to Infections
American Society for Microbiology, 2003

Sandler Program in Asthma Research Award, 2005

Service

NIH ALY study section member, 1992-1996;
miscellaneous NIH study sections, ad hoc 2002-2006 annually; chair, 2003, 2004, 2005; NCI intramural site visit reviewer 2000, 2005
Journal of Immunology, Associate Editor, 1991-1993, Section Editor, 1994-1998
Molecular Cell. Biology, Editorial Board, 1997 - present
National Multiple Sclerosis Society, Study Section Member, 1997 to 2002
Wellcome Trust Elion-Hitchings Fellowship Advisory Committee, 1998-2002
American Association of Immunologists, Publication Committee, 1999-2003
Reviewer: Nature, Science, Cell, Nature Immunol., Nature Neuro., Nature Rev. Immunol., Immunity, Mol. Cell., J. Exp. Med., Proc. Natl. Acad. Sci., Mol. Cell. Biol.,J. Immunol., J. Biol. Chem., Trends in Immunol.

Affiliations

Co-Director, Inflammatory Diseases Institute
Director, Center for Translational Immunology
Program Leader, Lineberger Comprehensive Cancer Center
UCRF Program Planning Committee

Department of Microbiology-Immunology
Lineberger Comprehensive Cancer Center
The Curriculum in Neurobiology
Curriculum in Genetics and Molecular Biology (CGMB)
Biological and Biomedical Sciences Program (BBSP)