Julie Zikherman, MD
Professor
Medicine
School of Medicine

(a) Our lab seeks to define the rules and mechanisms that govern B cell responses to specific features of self and foreign antigens, including antigen affinity, valency, biophysical structure, and co-stimulatory signals. We want to understand how self-reactive B cells, despite chronic antigen engagement of the B cell antigen receptor (BCR), are restrained from inappropriate activation and differentiation into antibody-secreting plasma cells. Conversely, we aim to determine how virus-like antigens bypass B cell tolerance. We want to define how this process is disrupted in a variety of autoimmune disease states, and how normal regulatory mechanisms (both biochemical and transcriptional) can be harnessed to restore tolerance on the one hand or optimize vaccine responses on the other.

(b) We are also interested in how developing T cells in the thymus interpret self antigen encounter in order to adopt distinct fates according to the type and intensity of signals received through the T cell antigen receptor (TCR) : deletion, diversion into regulatory lineages, or entry into the mature conventional T cell repertoire. We are also probing how thymocytes adapt and tune their signaling machinery to optimize affinity discrimination and limit inappropriate responses to self.

Our lab takes a range of approaches that span mouse genetics, cellular immunology, signal transduction, and genomics in order to address these questions. In particular, we have characterized and exploited reporter mice (NUR77-eGFP BAC transgenic) in which antigen receptor signaling drives expression of eGFP. This reporter serves as an in vivo sensor of both self and foreign antigen encounter, and serves to unmask enormous clonal heterogeneity among superficially uniform populations of lymphocytes.

• An Integrated Signaling Threshold Initiates IgG Response toward Virus-like Immunogens.
  Journal of immunology (Baltimore, Md. : 1950) 2024 Wholey WY, Meyer AR, Yoda ST, Mueller JL, Mathenge R, Chackerian B, Zikherman J, Cheng W
• Transcobalamin receptor antibodies in autoimmune vitamin B12 central deficiency.
  Science translational medicine 2024 Pluvinage JV, Ngo T, Fouassier C, McDonagh M, Holmes BB, Bartley CM, Kondapavulur S, Hurabielle C, Bodansky A, Pai V, Hinman S, Aslanpour A, Alvarenga BD, Zorn KC, Zamecnik C, McCann A, Asencor AI, …
• Minimal Determinants for Lifelong Antiviral Antibody Responses in Mice from a Single Exposure to Virus-like Immunogens at Low Doses.
  Vaccines 2024 Wholey WY, Meyer AR, Yoda ST, Chackerian B, Zikherman J, Cheng W
• Validation of a murine proteome-wide phage display library for identification of autoantibody specificities.
  JCI insight 2023 Rackaityte E, Proekt I, Miller HS, Ramesh A, Brooks JF, Kung AF, Mandel-Brehm C, Yu D, Zamecnik CR, Bair R, Vazquez SE, Sunshine S, Abram CL, Lowell CA, Rizzuto G, Wilson MR, Zikherman J, Anderson MS,…
• Nr4a nuclear receptors: markers and modulators of antigen receptor signaling.
  Current opinion in immunology 2023 Bending D, Zikherman J
• Many Achilles' heels of B and T cell tolerance.
  Immunological reviews 2022 Pelanda R, Zikherman J
• Establishment of fetomaternal tolerance through glycan-mediated B cell suppression.
  Nature 2022 Rizzuto G, Brooks JF, Tuomivaara ST, McIntyre TI, Ma S, Rideaux D, Zikherman J, Fisher SJ, Erlebacher A
• NR4A nuclear receptors in T and B lymphocytes: Gatekeepers of immune tolerance.
  Immunological reviews 2022 Hiwa R, Brooks JF, Mueller JL, Nielsen HV, Zikherman J
• Interferon gamma constrains type 2 lymphocyte niche boundaries during mixed inflammation.
  Immunity 2022 Cautivo KM, Matatia PR, Lizama CO, Mroz NM, Dahlgren MW, Yu X, Sbierski-Kind J, Taruselli MT, Brooks JF, Wade-Vallance A, Caryotakis SE, Chang AA, Liang HE, Zikherman J, Locksley RM, Molofsky AB
• ATP-competitive partial antagonists of the IRE1α RNase segregate outputs of the UPR.
  Nature chemical biology 2021 Feldman HC, Ghosh R, Auyeung VC, Mueller JL, Kim JH, Potter ZE, Vidadala VN, Perera BGK, Olivier A, Backes BJ, Zikherman J, Papa FR, Maly DJ
• NR4A family members regulate T cell tolerance to preserve immune homeostasis and suppress autoimmunity.
  JCI insight 2021 Hiwa R, Nielsen HV, Mueller JL, Mandla R, Zikherman J
• Negative feedback by NUR77/Nr4a1 restrains B cell clonal dominance during early T-dependent immune responses.
  Cell reports 2021 Brooks JF, Tan C, Mueller JL, Hibiya K, Hiwa R, Vykunta V, Zikherman J
• The BAFFling persistence of memory B cells.
  The Journal of experimental medicine 2021 Brooks JF, Zikherman J
• Synthetic Liposomal Mimics of Biological Viruses for the Study of Immune Responses to Infection and Vaccination.
  Bioconjugate chemistry 2020 Wholey WY, Mueller JL, Tan C, Brooks JF, Zikherman J, Cheng W
• Self-reactivity on a spectrum: A sliding scale of peripheral B cell tolerance.
  Immunological reviews 2019 Tan C, Noviski M, Huizar J, Zikherman J
• Long-Term Corticosteroid-Sparing Immunosuppression for Cardiac Sarcoidosis.
  Journal of the American Heart Association 2019 Rosenthal DG, Parwani P, Murray TO, Petek BJ, Benn BS, De Marco T, Gerstenfeld EP, Janmohamed M, Klein L, Lee BK, Moss JD, Scheinman MM, Hsia HH, Selby V, Koth LL, Pampaloni MH, Zikherman J, Vedantham…
• Reporters of TCR signaling identify arthritogenic T cells in murine and human autoimmune arthritis.
  Proceedings of the National Academy of Sciences of the United States of America 2019 Ashouri JF, Hsu LY, Yu S, Rychkov D, Chen Y, Cheng DA, Sirota M, Hansen E, Lattanza L, Zikherman J, Weiss A
• Optimal Development of Mature B Cells Requires Recognition of Endogenous Antigens.
  Journal of immunology (Baltimore, Md. : 1950) 2019 Noviski M, Tan C, Huizar J, Vykunta V, Mueller JL, Zikherman J
• GC B cells 'AKT' to blunt BCR signaling.
  Nature immunology 2019 Zikherman J
• Nur77 Links Chronic Antigen Stimulation to B Cell Tolerance by Restricting the Survival of Self-Reactive B Cells in the Periphery.
  Journal of immunology (Baltimore, Md. : 1950) 2019 Tan C, Mueller JL, Noviski M, Huizar J, Lau D, Dubinin A, Molofsky A, Wilson PC, Zikherman J
• Control of autoreactive B cells by IgM and IgD B cell receptors: maintaining a fine balance.
  Current opinion in immunology 2018 Noviski M, Zikherman J
• Nur77 Is Upregulated in B-1a Cells by Chronic Self-Antigen Stimulation and Limits Generation of Natural IgM Plasma Cells.
  ImmunoHorizons 2017 Huizar J, Tan C, Noviski M, Mueller JL, Zikherman J
• B cell autoimmunity at the extremes.
  Nature immunology 2017 Zikherman J, Lowell CA
• Tonic Signals: Why Do Lymphocytes Bother?
  Trends in immunology 2017 Myers DR, Zikherman J, Roose JP
• Tonic LAT-HDAC7 Signals Sustain Nur77 and Irf4 Expression to Tune Naive CD4 T Cells.
  Cell reports 2017 Myers DR, Lau T, Markegard E, Lim HW, Kasler H, Zhu M, Barczak A, Huizar JP, Zikherman J, Erle DJ, Zhang W, Verdin E, Roose JP
• IL-2 Modulates the TCR Signaling Threshold for CD8 but Not CD4 T Cell Proliferation on a Single-Cell Level.
  Journal of immunology (Baltimore, Md. : 1950) 2017 Au-Yeung BB, Smith GA, Mueller JL, Heyn CS, Jaszczak RG, Weiss A, Zikherman J
• An extracatalytic function of CD45 in B cells is mediated by CD22.
  Proceedings of the National Academy of Sciences of the United States of America 2015 Coughlin S, Noviski M, Mueller JL, Chuwonpad A, Raschke WC, Weiss A, Zikherman J
• Unbiased modifier screen reveals that signal strength determines the regulatory role murine TLR9 plays in autoantibody production.
  Journal of immunology (Baltimore, Md. : 1950) 2015 Mills RE, Lam VC, Tan A, Cresalia N, Oksenberg N, Zikherman J, Anderson M, Weiss A, Hermiston ML
• Cutting edge: An in vivo reporter reveals active B cell receptor signaling in the germinal center.
  Journal of immunology (Baltimore, Md. : 1950) 2015 Mueller J, Matloubian M, Zikherman J
• The role of T cell receptor signaling thresholds in guiding T cell fate decisions.
  Current opinion in immunology 2015 Zikherman J, Au-Yeung B
• A sharp T-cell antigen receptor signaling threshold for T-cell proliferation.
  Proceedings of the National Academy of Sciences of the United States of America 2014 Au-Yeung BB, Zikherman J, Mueller JL, Ashouri JF, Matloubian M, Cheng DA, Chen Y, Shokat KM, Weiss A
• Quantitative and temporal requirements revealed for Zap70 catalytic activity during T cell development.
  Nature immunology 2014 Au-Yeung BB, Melichar HJ, Ross JO, Cheng DA, Zikherman J, Shokat KM, Robey EA, Weiss A
• Protein kinase Cδ promotes transitional B cell-negative selection and limits proximal B cell receptor signaling to enforce tolerance.
  Molecular and cellular biology 2014 Limnander A, Zikherman J, Lau T, Leitges M, Weiss A, Roose JP
• Novel tools to dissect the dynamic regulation of TCR signaling by the kinase Csk and the phosphatase CD45.
  Cold Spring Harbor symposia on quantitative biology 2013 Tan YX, Zikherman J, Weiss A
• The structural wedge domain of the receptor-like tyrosine phosphatase CD45 enforces B cell tolerance by regulating substrate specificity.
  Journal of immunology (Baltimore, Md. : 1950) 2013 Zikherman J, Parameswaran R, Hermiston M, Weiss A
• Monovalent and multivalent ligation of the B cell receptor exhibit differential dependence upon Syk and Src family kinases.
  Science signaling 2013 Mukherjee S, Zhu J, Zikherman J, Parameswaran R, Kadlecek TA, Wang Q, Au-Yeung B, Ploegh H, Kuriyan J, Das J, Weiss A
• Endogenous antigen tunes the responsiveness of naive B cells but not T cells.
  Nature 2012 Zikherman J, Parameswaran R, Weiss A
• Quantitative differences in CD45 expression unmask functions for CD45 in B-cell development, tolerance, and survival.
  Proceedings of the National Academy of Sciences of the United States of America 2011 Zikherman J, Doan K, Parameswaran R, Raschke W, Weiss A
• Unraveling the functional implications of GWAS: how T cell protein tyrosine phosphatase drives autoimmune disease.
  The Journal of clinical investigation 2011 Zikherman J, Weiss A
• CD45-Csk phosphatase-kinase titration uncouples basal and inducible T cell receptor signaling during thymic development.
  Immunity 2010 Zikherman J, Jenne C, Watson S, Doan K, Raschke W, Goodnow CC, Weiss A
• Molecular origin and functional consequences of digital signaling and hysteresis during Ras activation in lymphocytes.
  Science signaling 2009 Chakraborty AK, Das J, Zikherman J, Yang M, Govern CC, Ho M, Weiss A, Roose J
• PTPN22 deficiency cooperates with the CD45 E613R allele to break tolerance on a non-autoimmune background.
  Journal of immunology (Baltimore, Md. : 1950) 2009 Zikherman J, Hermiston M, Steiner D, Hasegawa K, Chan A, Weiss A
• CD45, CD148, and Lyp/Pep: critical phosphatases regulating Src family kinase signaling networks in immune cells.
  Immunological reviews 2009 Hermiston ML, Zikherman J, Zhu JW
• Antigen receptor signaling in the rheumatic diseases.
  Arthritis research & therapy 2009 Zikherman J, Weiss A
• Digital signaling and hysteresis characterize ras activation in lymphoid cells.
  Cell 2009 Das J, Ho M, Zikherman J, Govern C, Yang M, Weiss A, Chakraborty AK, Roose JP
• Differential impact of the CD45 juxtamembrane wedge on central and peripheral T cell receptor responses.
  Proceedings of the National Academy of Sciences of the United States of America 2009 Hermiston ML, Zikherman J, Tan AL, Lam VC, Cresalia NM, Oksenberg N, Goren N, Brassat D, Oksenberg JR, Weiss A
• Alternative splicing of CD45: the tip of the iceberg.
  Immunity 2008 Zikherman J, Weiss A
• Origin of the sharp boundary that discriminates positive and negative selection of thymocytes.
  Proceedings of the National Academy of Sciences of the United States of America 2008 Prasad A, Zikherman J, Das J, Roose JP, Weiss A, Chakraborty AK