Julie Zikherman, MD

Professor in Residence
Medicine
--

Our laboratory is interested in understanding how B cell behavior is regulated after encounter with either “self” or “foreign” antigens. We postulate that overlapping mechanisms are at play in both scenarios. The lab seeks to define the rules that govern B cell responses to specific features of foreign antigens, including antigen affinity, valency and co-stimulatory signals. We are also interested in how the clonal composition of both the pre- and post-immune B cell repertoires is regulated. Against this backdrop, we want to understand how self-reactive B cells, despite chronic antigen engagement of the B cell receptor, are restrained from inappropriate activation and differentiation into antibody-secreting plasma cells. 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 and optimize vaccine responses.

To do so, our lab takes a range of creative approaches that span mouse genetics, cellular immunology, and genomics in order to address these questions. In particular, we have characterized and exploited novel reporter mice (NUR77-eGFP BAC transgenic) in which B cell 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 B cells. Recent work has focused on dissecting the distinct roles of the IgM and IgD B cell receptor isotypes in regulating the immune responses of self-reactive B cells. Newer projects seek to define how NUR77 and related orphan nuclear hormone receptors of the NR4A family function to restrain activation of chronically antigen-activated B cells and to regulate B responses to foreign antigen.

Publications: 

Mechanisms of neutralizing antibody response probed using synthetic virus-like structures.

bioRxiv : the preprint server for biology

Wholey WY, Meyer AR, Yoda ST, Chackerian B, Zikherman J, Cheng W

An integrated signaling threshold initiates IgG response towards virus-like immunogens.

bioRxiv : the preprint server for biology

Wholey WY, Meyer AR, Yoda ST, Mueller JL, Mathenge R, Chackerian B, Zikherman J, Cheng W

Validation of a murine proteome-wide phage display library for identification of autoantibody specificities.

JCI insight

Rackaityte E, Proekt I, Miller HS, Ramesh A, Brooks JF, Kung AF, Mandel-Brehm C, Yu DJ, Zamecnik CR, Bair R, Vazquez SE, Sunshine S, Abram CL, Lowell CA, Rizzuto G, Wilson MR, Zikherman J, Anderson MS, DeRisi JL

Molecular basis for potent B cell responses to antigen displayed on particles of viral size.

Nature immunology

Brooks JF, Riggs J, Mueller JL, Mathenge R, Wholey WY, Meyer AR, Yoda ST, Vykunta VS, Nielsen HV, Cheng W, Zikherman J

Validation of a murine proteome-wide phage display library for the identification of autoantibody specificities.

bioRxiv : the preprint server for biology

Rackaityte E, Proekt I, Miller HS, Ramesh A, Brooks JF, Kung AF, Mandel-Brehm C, Yu D, Zamecnik C, Bair R, Vazquez SE, Sunshine S, Abram CL, Lowell CA, Rizzuto G, Wilson MR, Zikherman J, Anderson MS, DeRisi JL

Molecular basis for potent B cell responses to antigen displayed on particles of viral size.

bioRxiv : the preprint server for biology

Brooks JF, Riggs J, Mueller JL, Mathenge R, Wholey WY, Yoda ST, Vykunta V, Cheng W, Zikherman J

Nr4a nuclear receptors: markers and modulators of antigen receptor signaling.

Current opinion in immunology

Bending D, Zikherman J

Many Achilles' heels of B and T cell tolerance.

Immunological reviews

Pelanda R, Zikherman J

Establishment of fetomaternal tolerance through glycan-mediated B cell suppression.

Nature

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

Hiwa R, Brooks JF, Mueller JL, Nielsen HV, Zikherman J

Interferon gamma constrains type 2 lymphocyte niche boundaries during mixed inflammation.

Immunity

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

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

Negative feedback by NUR77/Nr4a1 restrains B cell clonal dominance during early T-dependent immune responses.

Cell reports

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

Brooks JF, Zikherman J

NR4A nuclear receptors restrain B cell responses to antigen when second signals are absent or limiting.

Nature immunology

Tan C, Hiwa R, Mueller JL, Vykunta V, Hibiya K, Noviski M, Huizar J, Brooks JF, Garcia J, Heyn C, Li Z, Marson A, Zikherman J

Synthetic Liposomal Mimics of Biological Viruses for the Study of Immune Responses to Infection and Vaccination.

Bioconjugate chemistry

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

Tan C, Noviski M, Huizar J, Zikherman J

Long-Term Corticosteroid-Sparing Immunosuppression for Cardiac Sarcoidosis.

Journal of the American Heart Association

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 V

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

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)

Noviski M, Tan C, Huizar J, Vykunta V, Mueller JL, Zikherman J

GC B cells 'AKT' to blunt BCR signaling.

Nature immunology

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)

Tan C, Mueller JL, Noviski M, Huizar J, Lau D, Dubinin A, Molofsky A, Wilson PC, Zikherman J

IgM and IgD B cell receptors differentially respond to endogenous antigens and control B cell fate.

eLife

Noviski M, Mueller JL, Satterthwaite A, Garrett-Sinha LA, Brombacher F, Zikherman J

B cell autoimmunity at the extremes.

Nature immunology

Zikherman J, Lowell CA

Tonic Signals: Why Do Lymphocytes Bother?

Trends in immunology

Myers DR, Zikherman J, Roose JP

Tonic LAT-HDAC7 Signals Sustain Nur77 and Irf4 Expression to Tune Naive CD4 T Cells.

Cell reports

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)

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

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)

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)

Mueller J, Matloubian M, Zikherman J

The role of T cell receptor signaling thresholds in guiding T cell fate decisions.

Current opinion in immunology

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

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

Au-Yeung BB, Melichar HJ, Ross JO, Cheng DA, Zikherman J, Shokat KM, Robey EA, Weiss A

Protein kinase Cd promotes transitional B cell-negative selection and limits proximal B cell receptor signaling to enforce tolerance.

Molecular and cellular biology

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

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)

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

Mukherjee S, Zhu J, Zikherman J, Parameswaran R, Kadlecek TA, Wang Q, Au-Yeung B, Ploegh H, Kuriyan J, Das J, 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

Zikherman J, Doan K, Parameswaran R, Raschke W, Weiss A

CD45-Csk phosphatase-kinase titration uncouples basal and inducible T cell receptor signaling during thymic development.

Immunity

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

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)

Zikherman J, Hermiston M, Steiner D, Hasegawa K, Chan A, Weiss A

Antigen receptor signaling in the rheumatic diseases.

Arthritis research & therapy

Zikherman J, Weiss A

Digital signaling and hysteresis characterize ras activation in lymphoid cells.

Cell

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

Hermiston ML, Zikherman J, Tan AL, Lam VC, Cresalia NM, Oksenberg N, Goren N, Brassat D, Oksenberg JR, 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

Prasad A, Zikherman J, Das J, Roose JP, Weiss A, Chakraborty AK