Martin S. Naradikian
University of Pennsylvania
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Featured researches published by Martin S. Naradikian.
Blood | 2011
Yi Hao; Patrick J. O'Neill; Martin S. Naradikian; Jean L. Scholz; Michael P. Cancro
We have discovered a distinct mature B-cell subset that accumulates with age, which we have termed age-associated B cells. These cells comprise up to 30% of mature B cells by 22 months. Despite sharing some features with other mature B-cell subsets, they are refractory to BCR and CD40 stimulation. Instead, they respond to TLR9 or TLR7 stimulation and divide maximally on combined BCR and TLR ligation, leading to Ig production and preferential secretion of IL-10 and IL-4. Although similar to follicular B cells in both B-lymphocyte stimulator (BLyS) receptor expression and BLyS binding capacity, these cells do not rely on BLyS for survival. They are neither cycling nor the result of intrinsically altered B lymphopoiesis in aged BM, but instead appear to be generated from mature B cells that exhaustively expand during the individuals lifetime. Finally, they present Ag effectively and favor polarization to a TH17 profile. Together, these findings reveal that while the magnitude of the mature primary B-cell niche is maintained with age, it is increasingly occupied by cells refractory to BCR-driven activation yet responsive to innate receptor stimulation.
Immunological Reviews | 2016
Martin S. Naradikian; Yi Hao; Michael P. Cancro
A subset of B cells with unique phenotypic and functional features—termed Age‐associated B cells (ABCs)—has recently been identified in both mice and humans. These cells are characterized by a T‐BET driven transcriptional program, robust responsiveness to TLR7 and TLR9 ligands, and a propensity for IgG2a/c production. Beyond their age‐related accumulation, these cells play roles in both normal and pathogenic humoral immune responses regardless of host age. Thus, B cells with the ABC phenotype and transcriptional signature appear during viral, bacterial, and parasitic infections, but also arise during humoral autoimmune disease in both mouse models and humans. These observations suggest that both autoantigens and certain classes of pathogens provide the signals required for ABC differentiation. Herein, we review the discovery and features of ABCs, and propose that they are a memory subset generated by nucleic acid‐containing antigens in the context of a promoting inflammatory cytokine milieu.
Journal of Immunology | 2016
Martin S. Naradikian; Arpita Myles; Daniel P. Beiting; Kenneth J. Roberts; Lucas Dawson; Ramin S. Herati; Bertram Bengsch; Susanne L. Linderman; Erietta Stelekati; Rosanne Spolski; E. John Wherry; Christopher A. Hunter; Scott E. Hensley; Warren J. Leonard; Michael P. Cancro
T-bet and CD11c expression in B cells is linked with IgG2c isotype switching, virus-specific immune responses, and humoral autoimmunity. However, the activation requisites and regulatory cues governing T-bet and CD11c expression in B cells remain poorly defined. In this article, we reveal a relationship among TLR engagement, IL-4, IL-21, and IFN-γ that regulates T-bet expression in B cells. We find that IL-21 or IFN-γ directly promote T-bet expression in the context of TLR engagement. Further, IL-4 antagonizes T-bet induction. Finally, IL-21, but not IFN-γ, promotes CD11c expression independent of T-bet. Using influenza virus and Heligmosomoides polygyrus infections, we show that these interactions function in vivo to determine whether T-bet+ and CD11c+ B cells are formed. These findings suggest that T-bet+ B cells seen in health and disease share the common initiating features of TLR-driven activation within this circumscribed cytokine milieu.
Journal of Immunology | 2017
Lisa M. Russell Knode; Martin S. Naradikian; Arpita Myles; Jean L. Scholz; Yi Hao; Danya Liu; Mandy L. Ford; John W. Tobias; Michael P. Cancro; Patricia J. Gearhart
The origin and nature of age-associated B cells (ABCs) in mice are poorly understood. In this article, we show that their emergence required MHC class II and CD40/CD40L interactions. Young donor B cells were adoptively transferred into congenic recipients and allowed to remain for 1 mo in the absence of external Ag. B cells expressing the T-bet transcription factor, a marker for ABCs, were generated after multiple cell divisions from C57BL/6 donors but not from MHC class II– or CD40-deficient donors. Furthermore, old CD154 (CD40L)-deficient mice did not accrue ABCs, confirming that they arise primarily through T-dependent interactions. To determine what Igs ABCs express, we sequenced VH and Vκ rearranged genes from unimmunized 22-mo-old C57BL/6 mice and showed that they had a heterogeneous repertoire, which was comparable to that seen in old follicular and marginal zone B cell subsets. However, in contrast to the follicular and marginal zone cells, ABCs displayed significant somatic hypermutation. The mutation frequency was lower than found in germinal center cells after deliberate immunization, suggesting that ABCs have undergone mild stimulation from endogenous Ags over time. These observations show that quiescent ABCs are Ag-experienced cells that accumulate during T cell–dependent responses to diverse Ags during the life of an individual.
Current Opinion in Immunology | 2015
Martin S. Naradikian; Alison R. Perate; Michael P. Cancro
The BAFF family of receptors and ligands controls B cell homeostasis and selection. Recent studies reveal distinct sources and roles for systemic versus locally produced BAFF. Moreover, the notion that differential BAFF receptor expression patterns establish independent homeostatic and selective niches has been strengthened. Finally, unique roles for BAFF family members in the regulation of antigen experienced and innate B cell subsets have been revealed. Herein, we overview current knowledge in these areas, emphasizing recent findings that inform these ideas.
Experimental Gerontology | 2014
Radhika Goenka; Jean L. Scholz; Martin S. Naradikian; Michael P. Cancro
We examined whether age alters the emergence of high-affinity germinal center B (GCB) cells and switched memory B cells (swBmem) during a primary immune response to a thymus-dependent antigen, using a novel flow cytometric assay to distinguish relative BCR affinity. In young mice, high-affinity B cells predominate in the GCB pool and comprise a smaller proportion of the nascent swBmem pool two weeks after immunization. In aged mice, we observe significant reductions of high-affinity clones among GCB cells, but not nascent swBmem cells. The defect in GC affinity maturation was not overcome by providing excess carrier-specific T cells from young mice, as these cells still displayed compromised effector TFH differentiation in the aged animals. Our results suggest that B cells in aged animals have a reduced ability to prompt effector TFH differentiation, leading to a compromised GC response that results in reduced generation of high-affinity GCB and plasma cells; despite normal production of early swBmem cells.
Journal of Immunology | 2012
Divya Punwani; Karen L. Simon; Youngnim Choi; Amalia Dutra; Diana Gonzalez-Espinosa; Evgenia Pak; Martin S. Naradikian; Jenny Y. Zhang; David M. Bodine; Jennifer M. Puck
Absent T lymphocytes were unexpectedly found in homozygotes of a transgenic mouse from an unrelated project. T cell development did not progress beyond double-negative stage 1 thymocytes, resulting in a hypocellular, vestigial thymus. B cells were present, but NK cell number and B cell isotype switching were reduced. Transplantation of wild-type hematopoietic cells corrected the defect, which was traced to a deletion involving five contiguous genes at the transgene insertion site on chromosome 12C3. Complementation using bacterial artificial chromosome transgenesis implicated zinc finger BTB-POZ domain protein 1 (Zbtb1) in the immunodeficiency, confirming its role in T cell development and suggesting involvement in B and NK cell differentiation. Targeted disruption of Zbtb1 recapitulated the T−B+NK− SCID phenotype of the original transgenic animal. Knockouts for Zbtb1 had expanded populations of bone marrow hematopoietic stem cells and also multipotent and early lymphoid lineages, suggesting a differentiation bottleneck for common lymphoid progenitors. Expression of mRNA encoding Zbtb1, a predicted transcription repressor, was greatest in hematopoietic stem cells, thymocytes, and pre-B cells, highlighting its essential role in lymphoid development.
Journal of Clinical Investigation | 2017
Vishal J. Sindhava; Michael A. Oropallo; Krishna Moody; Martin S. Naradikian; Lauren E. Higdon; Lin Zhou; Arpita Myles; Nathaniel M. Green; Kerstin Nundel; William Stohl; Amanda M. Schmidt; Wei Cao; Stephanie Dorta-Estremera; Taku Kambayashi; Ann Marshak-Rothstein; Michael P. Cancro
Mature B cell pools retain a substantial proportion of polyreactive and self-reactive clonotypes, suggesting that activation checkpoints exist to reduce the initiation of autoreactive B cell responses. Here, we have described a relationship among the B cell receptor (BCR), TLR9, and cytokine signals that regulate B cell responses to DNA-containing antigens. In both mouse and human B cells, BCR ligands that deliver a TLR9 agonist induce an initial proliferative burst that is followed by apoptotic death. The latter mechanism involves p38-dependent G1 cell-cycle arrest and subsequent intrinsic mitochondrial apoptosis and is shared by all preimmune murine B cell subsets and CD27– human B cells. Survival or costimulatory signals rescue B cells from this fate, but the outcome varies depending on the signals involved. B lymphocyte stimulator (BLyS) engenders survival and antibody secretion, whereas CD40 costimulation with IL-21 or IFN-&ggr; promotes a T-bet+ B cell phenotype. Finally, in vivo immunization studies revealed that when protein antigens are conjugated with DNA, the humoral immune response is blunted and acquires features associated with T-bet+ B cell differentiation. We propose that this mechanism integrating BCR, TLR9, and cytokine signals provides a peripheral checkpoint for DNA-containing antigens that, if circumvented by survival and differentiative cues, yields B cells with the autoimmune-associated T-bet+ phenotype.
Journal of Immunology | 2015
Amy DeMicco; Martin S. Naradikian; Vishal J. Sindhava; Je-Hyun Yoon; Myriam Gorospe; Gerald Wertheim; Michael P. Cancro; Craig H. Bassing
The HuR RNA-binding protein posttranscriptionally controls expression of genes involved in cellular survival, proliferation, and differentiation. To determine roles of HuR in B cell development and function, we analyzed mice with B lineage–specific deletion of the HuR gene. These HuRΔ/Δ mice have reduced numbers of immature bone marrow and mature splenic B cells, with only the former rescued by p53 inactivation, indicating that HuR supports B lineage cells through developmental stage-specific mechanisms. Upon in vitro activation, HuRΔ/Δ B cells have a mild proliferation defect and impaired ability to produce mRNAs that encode IgH chains of secreted Abs, but no deficiencies in survival, isotype switching, or expression of germinal center (GC) markers. In contrast, HuRΔ/Δ mice have minimal serum titers of all Ab isotypes, decreased numbers of GC and plasma B cells, and few peritoneal B-1 B cells. Moreover, HuRΔ/Δ mice have severely decreased GCs, T follicular helper cells, and high-affinity Abs after immunization with a T cell–dependent Ag. This failure of HuRΔ/Δ mice to mount a T cell–dependent Ab response contrasts with the ability of HuRΔ/Δ B cells to become GC-like in vitro, indicating that HuR is essential for aspects of B cell activation unique to the in vivo environment. Consistent with this notion, we find in vitro stimulated HuRΔ/Δ B cells exhibit modestly reduced surface expression of costimulatory molecules whose expression is similarly decreased in humans with common variable immunodeficiency. HuRΔ/Δ mice provide a model to identify B cell–intrinsic factors that promote T cell–dependent immune responses in vivo.
Journal of Experimental Medicine | 2018
Norbert Pardi; Michael J. Hogan; Martin S. Naradikian; Kaela Parkhouse; Derek W. Cain; Letitia Jones; M. Anthony Moody; Hans Verkerke; Arpita Myles; Elinor Willis; Celia C. LaBranche; David C. Montefiori; Jenna Lobby; Kevin O. Saunders; Hua-Xin Liao; Bette Korber; Laura L. Sutherland; Richard M. Scearce; Peter Hraber; István Tombácz; Hiromi Muramatsu; Houping Ni; Daniel A Balikov; Charles Li; Barbara L. Mui; Ying K. Tam; Florian Krammer; Katalin Karikó; Patricia Polacino; Laurence C. Eisenlohr
T follicular helper (Tfh) cells are required to develop germinal center (GC) responses and drive immunoglobulin class switch, affinity maturation, and long-term B cell memory. In this study, we characterize a recently developed vaccine platform, nucleoside-modified, purified mRNA encapsulated in lipid nanoparticles (mRNA-LNPs), that induces high levels of Tfh and GC B cells. Intradermal vaccination with nucleoside-modified mRNA-LNPs encoding various viral surface antigens elicited polyfunctional, antigen-specific, CD4+ T cell responses and potent neutralizing antibody responses in mice and nonhuman primates. Importantly, the strong antigen-specific Tfh cell response and high numbers of GC B cells and plasma cells were associated with long-lived and high-affinity neutralizing antibodies and durable protection. Comparative studies demonstrated that nucleoside-modified mRNA-LNP vaccines outperformed adjuvanted protein and inactivated virus vaccines and pathogen infection. The incorporation of noninflammatory, modified nucleosides in the mRNA is required for the production of large amounts of antigen and for robust immune responses.