Lisa Denzin, PhD

Dr. Lisa Denzin is an Associate Professor of Pediatrics at the Child Health Institute of NJ, Rutgers Robert Wood Johnson Medical School. She received a BS degree in Medical Microbiology from the University of Wisconsin-Madison in 1987 and a PhD in Microbiology from the University of Illinois-Urbana in 1992. After 5 years of post-doctoral studies in Immunology under the tutelage of Dr. Peter Cresswell at Yale University, she was an Assistant Professor of Immunology at Duke University. In 1998 she moved her research laboratory to the Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center in Manhattan where she was an Assistant and then an Associate Member. She also held a joint appointment at the Weill Graduate School of Medical Sciences of Cornell University in Manhattan. Dr. Denzin joined the faculty of the Robert Wood Johnson Medical School in September 2011. Her research interests include the control of immunity and autoimmunity and also in the molecular control of hematopoiesis.

Adaptive immunity begins with the presentation of antigens in the context of MHC.  In our initial work, we showed that antigen presentation is controlled by the MHC class II like molecule, HLA-DM (H2-M in mice). We went on to show that the DM cofactor, HLA-DO (H2-O in mice), inhibits DM activity. Recent data from our lab shows that modulation of the MHCII antigen-processing pathway by DO can have profound immunological effects.  In particular, DO expression shapes the overall MHCII-peptide repertoire and, in doing so ultimately, controls immunity. 

• DO controls the neutralizing Ab response to retroviruses in mice.
• Mutations in several alleles of human HLA-DOA and HLA-DOB affected antigen presentation, a few can be genetically linked to the outcomes of hepatitis B and C infection
• Modulation of antigen processing and presentation by DM and DO is more complex than previously appreciated and data supports that factors in addition to DM and DO control the peptide loading of MHCII molecules. 

My lab combines biochemical, cell biological and immunological approaches to examine the role of HLA-DM and HLA-DO in two main research areas, both of which have high relevance to human disease.

First, we are engaged in two studies concerning Type 1 Diabetes (T1D). The etiology of T1D is strongly linked to genetic variations within major histocompatibility complex (MHC) class II (MHCII) locus, especially the human leukocyte antigen (HLA)-DR and HLA-DQ genes. Other genes in the class II locus, however, also contribute to the disease. Our collaborators in Sardinia, Italy undertook extensive, new T1D genetic association studies in an attempt to uncover these other players. Due to a founder effect quirk, Sardinians suffer from the second highest rate of T1D in the world, making this genetic pool well suited for these studies. These studies have identified an allele of HLA-DM (DM) that is associated with protection from T1D. The protective allele of DM has a bulky amino acid substitution that localizes to the interface between MHCII and DM, suggesting suboptimal MHCII-DM interactions. This leads us to hypothesize that protection from T1D in individuals expressing this DM allele is due to reduced activity, resulting in the presentation of an altered repertoire of MHCII-bound peptides. This idea is supported by our published studies, which showed that dampening DM activity by expression of DO in the DCs of Non-Obese Diabetic (NOD) mice is protective against T1D.

We also postulate that since DM and DO synergistically control peptide loading of MHCII molecules, these molecules may be differentially expressed (or different alleles expressed) in individuals that develop T1D versus those that do not. Studies are currently underway to measure DM and DO protein levels and sequencing the DM and DO genes form 100 T1D patients and 100 normal controls.  The results of these studies will determine if these molecules could function as biomarkers to identify patients in which disease interception would be optimal.  In the context of autoimmunity, understanding the interplay between DM, DO and MHCII antigen presentation has the potential to reveal a targetable means to suppress overaggressive T cell responsiveness to self-antigens.  Uncovering the means to enhance immunity to cancer and infectious disease would be a logical extension of these studies. 

The second focus of our work is on the surprising identification of H2-O as a retroviral restriction factor.  Most retroviral infections in mice result in indefinite viral persistence with an undetectable or inefficient anti-virus immune response.  Poor immune reactivity has made the elucidation of protective anti-retroviral pathways an incredibly arduous endeavor.  There are, however, rare individuals capable of mounting a potent anti-retroviral immune response, and the study of these individuals has allowed dissection of the protective responses.  For example, some Human Immunodeficiency Virus (HIV)-infected individuals termed ‘long-term or elite non-progressors’ are able to initiate and maintain robust anti-viral responses via specific genetic mechanisms.  My collaborator, Dr. Tatyana Golovkina (University of Chicago), discovered that I/LnJ mice, carry a recessive retrovirus resistance-conferring gene.  Unlike virus-susceptible mice, I/LnJ mice infected with retrovirus produce virus-neutralizing Abs that are sustained throughout their life.  Congenic and bacterial artificial chromosome (BAC) transgenic approaches implicated the beta chain of H2-O as the gene (H2-Ob) encoding for virus resistance.  Working together with Dr. Golovkina we have definitively shown that H2-O controls the neutralizing Ab response to retroviruses in I/LnJ mice.  Furthermore, our studies have shown that the Ob allele carried by I/LnJ is a null allele that, despite interacting with H2-M and properly localizing to endosomal compartments, does not inhibit MHCII presentation.  This is an unexpected finding that suggests H2-O may function via mechanisms that are yet to be discovered.  Therefore, our current research, seeks to reveal the mechanism by which H2-O controls the immune response to retroviruses. 

• Cullum E, Graves, AM, Tarakanova VL, Denzin LK, Golovkina TV.  MHC Class II presentation is affected by polymorphism in the H2-Ob gene and additional loci.  J Immunol. 2021 Jul 1;207(1):5-14. doi: 10.4049/jimmunol.2100061. PMID: 34135064

• Graves AM, VirdisF, MorrisonE, Álvaro-BenitoM, KhanAA, FreundC, GolovkinaTV, Denzin LK.  Human hepatitis B viral infection outcomes are linked to naturally occurring variants of HLA-DOA that have altered function.  J Immunol. 2020 Aug 15;205(4):923-935. doi: 10.4049/jimmunol.2000476. Epub 2020 Jul 20.  PMID: 32690655

• Denzin LK, Khan AA, Virdis F, Wilks J, Kane M, Beilinson HA, Dikiy S, Case LK, Roopenian D, Witkowski M, Chervonsky AV, Golovkina TV. Neutralizing Antibody Responses to Viral Infections Are Linked to the Non-classical MHC Class II Gene H2-Ob. Immunity. 2017;47(2):310-22 e7. Epub 2017/08/17. doi: 10.1016/j.immuni.2017.07.013. PubMed PMID: 28813660; PMCID: PMC5568092.

• Porter GW, Yi W, Denzin LK. TLR agonists downregulate H2-O in CD8alpha- dendritic cells. J Immunol. 2011;187(8):4151-60. Epub 2011/09/16. doi: 10.4049/jimmunol.1003137. PubMed PMID: 21918198; PMCID: PMC3186832.

• Draghi NA, Denzin LK. H2-O, a MHC class II-like protein, sets a threshold for B-cell entry into germinal centers. Proc Natl Acad Sci U S A. 2010;107(38):16607-12. Epub 2010/09/03. doi: 10.1073/pnas.1004664107. PubMed PMID: 20807742; PMCID: PMC2944729.