Publications by authors named "Irina L Grigorova"

12 Publications

  • Page 1 of 1

Signals 1, 2 and B cell fate or: Where, when and for how long?

Immunol Rev 2020 07 29;296(1):9-23. Epub 2020 May 29.

Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, USA.

Diverse B cell responses are important for generating antibody-mediated protection against highly variable pathogens. While some antigens can trigger T-independent B cell proliferation and short-term antibody production, development of long-term humoral immunity requires T-dependent B cell responses. The "two-signal" model of B cell activation has long been invoked to explain alternate B cell recruitment into immune response to foreign antigens vs. induction of tolerance to self-antigens. However, a number of other factors appear to influence the fate of mature B cells responding to antigen in vivo. In this review, we will discuss how various spatiotemporal scenarios of antigen access into secondary lymphoid organs, antigen valency and cellular environment of antigen acquisition by B cells, duration of B cell access to antigen and the timing of T cell help may affect follicular B cell fate, including death, survival, anergy, and recruitment into T-dependent responses. We will also highlight unresolved questions related to B cell activation and tolerance in vivo that may have important implications for vaccine development and autoimmunity.
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http://dx.doi.org/10.1111/imr.12865DOI Listing
July 2020

CCL3 Promotes Germinal Center B Cells Sampling by Follicular Regulatory T Cells in Murine Lymph Nodes.

Front Immunol 2018 13;9:2044. Epub 2018 Sep 13.

Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, United States.

Previous studies and our findings suggest upregulated expression of proinflammatory chemokines CCL3/4 in germinal center (GC) centrocytes. However, the role of CCL3/4 for centrocyte interactions with follicular T cells and regulation of humoral immunity is poorly understood. We found that CCL3 promotes chemotaxis of Tfr cells . Two-photon imaging revealed that B cells-intrinsic production of CCL3 promotes their probing by follicular regulatory T cells (Tfr) within GCs of murine lymph nodes. Overall this study suggests that CCL3 facilitates direct interactions of foreign antigen-specific GC B cells and their negative regulation with Tfr cells .
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http://dx.doi.org/10.3389/fimmu.2018.02044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6146081PMC
September 2019

TLR7-Mediated Lupus Nephritis Is Independent of Type I IFN Signaling.

J Immunol 2018 07 8;201(2):393-405. Epub 2018 Jun 8.

Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109;

Systemic lupus erythematosus is an autoimmune disease characterized by increased type I IFNs, autoantibodies, and inflammatory-mediated multiorgan damage. TLR7 activation is an important contributor to systemic lupus erythematosus pathogenesis, but the mechanisms by which type I IFNs participate in TLR7-driven pathologic conditions remain uncertain. In this study, we examined the requirement for type I IFNs in TLR7-stimulated lupus nephritis. Lupus-prone NZM2328, INZM (which lack a functional type I IFN receptor), and NZM2328 IL-1β mice were treated at 10 wk of age on the right ear with R848 (TLR7 agonist) or control (DMSO). Autoantibody production and proteinuria were assessed throughout treatment. Multiorgan inflammation was assessed at the time of decline in health. Renal infiltrates and mRNA expression were also examined after 14 d of treatment. Both NZM2328 and INZM mice exhibited a decline in survival after 3-4 wk of R848 but not vehicle treatment. Development of splenomegaly and liver inflammation were dependent on type I IFN. Interestingly, autoantibody production, early renal infiltration of dendritic cells, upregulation of IL-1β, and lupus nephritis occurred independent of type I IFN signaling. Development of TLR7-driven lupus nephritis was not abolished by the deletion of IL-1β. Thus, although IFN-α is sufficient to induce nephritis acceleration, our data emphasize a critical role for IFN-independent signaling in TLR7-mediated lupus nephritis. Further, despite upregulation of IL-1β after TLR7 stimulation, deletion of IL-1β is not sufficient to reduce lupus nephritis development in this model.
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http://dx.doi.org/10.4049/jimmunol.1701588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6039244PMC
July 2018

Antigen Acquisition Enables Newly Arriving B Cells To Enter Ongoing Immunization-Induced Germinal Centers.

J Immunol 2017 08 7;199(4):1301-1307. Epub 2017 Jul 7.

Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109-5620

Modern vaccines must be designed to generate long-lasting, high-affinity, and broadly neutralizing Ab responses against pathogens. The diversity of B cell clones recruited into germinal center (GC) responses is likely to be important for the Ag-neutralization potential of the Ab-secreting cells and memory cells generated upon immunization. However, the factors that influence the diversity of B cell clones recruited into GCs are unclear. As recirculating naive Ag-specific B cells arrive in Ag-draining secondary lymphoid organs, they may join the ongoing GC response. However, the factors that limit their entry are not well understood, and it is not known how that depends on the stage of the ongoing follicular T cell and GC B cell response. In this article, we show that, in mice, naive B cells have a limited window of time during which they can undergo Ag-driven activation and join ongoing immunization-induced GC responses. However, preloading naive B cells with even a threshold-activating amount of Ag is sufficient to rescue their entry into the GC response during its initiation, peak, and contraction. Based on these results, we suggest that productive acquisition of Ag may be one of the main factors limiting entry of new B cell clones into ongoing immunization-triggered GC responses.
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http://dx.doi.org/10.4049/jimmunol.1700267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5548600PMC
August 2017

Visualization of splenic marginal zone B-cell shuttling and follicular B-cell egress.

Nature 2013 Jan 23;493(7434):684-8. Epub 2012 Dec 23.

Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California, San Francisco, California 94143, USA.

The splenic marginal zone is a unique microenvironment where resident immune cells are exposed to the open blood circulation. Even though it has an important role in responses against blood-borne antigens, lymphocyte migration in the marginal zone has not been intravitally visualized due to challenges associated with achieving adequate imaging depth in this abdominal organ. Here we develop a two-photon microscopy procedure to study marginal zone and follicular B-cell movement in the live mouse spleen. We show that marginal zone B cells are highly motile and exhibit long membrane extensions. Marginal zone B cells shuttle between the marginal zone and follicles with at least one-fifth of the cells exchanging between compartments per hour, a behaviour that explains their ability to deliver antigens rapidly from the open blood circulation to the secluded follicles. Follicular B cells also transit from follicles to the marginal zone, but unlike marginal zone B cells, they fail to undergo integrin-mediated adhesion, become caught in fluid flow and are carried into the red pulp. Follicular B-cell egress via the marginal zone is sphingosine-1-phosphate receptor-1 (S1PR1)-dependent. This study shows that marginal zone B cells migrate continually between marginal zone and follicles and establishes the marginal zone as a site of S1PR1-dependent B-cell exit from follicles. The results also show how adhesive differences of similar cells critically influence their behaviour in the same microenvironment.
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http://dx.doi.org/10.1038/nature11738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3561487PMC
January 2013

Lymph node cortical sinus organization and relationship to lymphocyte egress dynamics and antigen exposure.

Proc Natl Acad Sci U S A 2010 Nov 8;107(47):20447-52. Epub 2010 Nov 8.

The Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California, San Francisco, CA 94143, USA.

Recent studies have identified cortical sinuses as sites of sphingosine-1-phosphate receptor-1 (S1P(1))-dependent T- and B-cell egress from the lymph node (LN) parenchyma. However, the distribution of cortical sinuses in the entire LN and the extent of lymph flow within them has been unclear. Using 3D reconstruction and intravital two-photon microscopy we describe the branched organization of the cortical sinus network within the inguinal LN and show that lymphocyte flow begins within blunt-ended sinuses. Many cortical sinuses are situated adjacent to high endothelial venules, and some lymphocytes access these sinuses within minutes of entering a LN. However, upon entry to inflamed LNs, lymphocytes rapidly up-regulate CD69 and are prevented from accessing cortical sinuses. Using the LN reconstruction data and knowledge of lymphocyte migration and cortical sinus entry dynamics, we developed a mathematical model of T-cell egress from LNs. The model suggests that random walk encounters with lymphatic sinuses are the major factor contributing to LN transit times. A slight discrepancy between predictions of the model and the measured transit times may be explained by lymphocytes undergoing a few rounds of migration between the parenchyma and sinuses before departing from the LN. Because large soluble antigens gain rapid access to cortical sinuses, such parenchyma-sinus shuttling may facilitate antibody responses.
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http://dx.doi.org/10.1073/pnas.1009968107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2996652PMC
November 2010

Cortical sinus probing, S1P1-dependent entry and flow-based capture of egressing T cells.

Nat Immunol 2009 Jan 7;10(1):58-65. Epub 2008 Dec 7.

Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California San Francisco, San Francisco, California 94143, USA.

The cellular dynamics of the egress of lymphocytes from lymph nodes are poorly defined. Here we visualized the branched organization of lymph node cortical sinuses and found that after entry, some T cells were retained, whereas others returned to the parenchyma. T cells deficient in sphingosine 1-phosphate receptor type 1 probed the sinus surface but failed to enter the sinuses. In some sinuses, T cells became rounded and moved unidirectionally. T cells traveled from cortical sinuses into macrophage-rich sinus areas. Many T cells flowed from medullary sinuses into the subcapsular space. We propose a multistep model of lymph node egress in which cortical sinus probing is followed by entry dependent on sphingosine 1-phosphate receptor type 1, capture of cells in a sinus region with flow, and transport to medullary sinuses and the efferent lymph.
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http://dx.doi.org/10.1038/ni.1682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2710451PMC
January 2009

The actin regulator coronin 1A is mutant in a thymic egress-deficient mouse strain and in a patient with severe combined immunodeficiency.

Nat Immunol 2008 Nov 5;9(11):1307-15. Epub 2008 Oct 5.

Howard Hughes Medical Institute, University of California San Francisco, San Francisco, California 94143, USA.

Mice carrying the recessive locus for peripheral T cell deficiency (Ptcd) have a block in thymic egress, but the mechanism responsible is undefined. Here we found that Ptcd T cells had an intrinsic migration defect, impaired lymphoid tissue trafficking and irregularly shaped protrusions. Characterization of the Ptcd locus showed a point substitution of lysine for glutamic acid at position 26 in the actin regulator coronin 1A that enhanced its inhibition of the actin regulator Arp2/3 and resulted in its mislocalization from the leading edge of migrating T cells. The discovery of another coronin 1A mutant during an N-ethyl-N-nitrosourea-mutagenesis screen for T cell-lymphopenic mice prompted us to evaluate a T cell-deficient, B cell-sufficient and natural killer cell-sufficient patient with severe combined immunodeficiency, whom we found had mutations in both CORO1A alleles. Our findings establish a function for coronin 1A in T cell egress, identify a surface of coronin involved in Arp2/3 regulation and demonstrate that actin regulation is a biological process defective in human and mouse severe combined immunodeficiency.
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http://dx.doi.org/10.1038/ni.1662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2672406PMC
November 2008

Design principles of the proteolytic cascade governing the sigmaE-mediated envelope stress response in Escherichia coli: keys to graded, buffered, and rapid signal transduction.

Genes Dev 2007 Jan;21(1):124-36

Department of Microbiology and Immunology, University of California at San Francisco, San Francisco, California 94158, USA.

Proteolytic cascades often transduce signals between cellular compartments, but the features of these cascades that permit efficient conversion of a biological signal into a transcriptional output are not well elucidated. sigma(E) mediates an envelope stress response in Escherichia coli, and its activity is controlled by regulated degradation of RseA, a membrane-spanning anti-sigma factor. Examination of the individual steps in this protease cascade reveals that the initial, signal-sensing cleavage step is rate-limiting; that multiple ATP-dependent proteases degrade the cytoplasmic fragment of RseA and that dissociation of sigma(E) from RseA is so slow that most free sigma(E) must be generated by the active degradation of RseA. As a consequence, the degradation rate of RseA is set by the amount of inducing signal, and insulated from the "load" on and activity of the cytoplasmic proteases. Additionally, changes in RseA degradation rate are rapidly reflected in altered sigma(E) activity. These design features are attractive as general components of signal transduction pathways governed by unstable negative regulators.
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http://dx.doi.org/10.1101/gad.1496707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1759897PMC
January 2007

Insights into transcriptional regulation and sigma competition from an equilibrium model of RNA polymerase binding to DNA.

Proc Natl Acad Sci U S A 2006 Apr 27;103(14):5332-7. Epub 2006 Mar 27.

Graduate Group in Biophysics and Department of Microbiology, University of California-San Francisco, 600 16th Street, Genentech Hall, Box 2200, San Francisco, CA 94143, USA.

To explore scenarios that permit transcription regulation by activator recruitment of RNA polymerase and sigma competition in vivo, we used an equilibrium model of RNA polymerase binding to DNA constrained by the values of total RNA polymerase (E) and sigma(70) per cell measured in this work. Our numbers of E and sigma(70) per cell, which are consistent with most of the primary data in the literature, suggest that in vivo (i) only a minor fraction of RNA polymerase (<20%) is involved in elongation and (ii) sigma(70) is in excess of total E. Modeling the partitioning of RNA polymerase between promoters, nonspecific DNA binding sites, and the cytoplasm suggested that even weak promoters will be saturated with Esigma(70) in vivo unless nonspecific DNA binding by Esigma(70) is rather significant. In addition, the model predicted that sigmas compete for binding to E only when their total number exceeds the total amount of RNA polymerase (excluding that involved in elongation) and that weak promoters will be preferentially subjected to sigma competition.
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http://dx.doi.org/10.1073/pnas.0600828103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1459355PMC
April 2006

Fine-tuning of the Escherichia coli sigmaE envelope stress response relies on multiple mechanisms to inhibit signal-independent proteolysis of the transmembrane anti-sigma factor, RseA.

Genes Dev 2004 Nov;18(21):2686-97

Graduate Group in Biophysics, University of California, San Francisco, San Francisco, California 94143, USA.

Proteolytic cascades are widely implicated in signaling between cellular compartments. In Escherichia coli, accumulation of unassembled outer membrane porins (OMPs) in the envelope leads to expression of sigma(E)-dependent genes in the cytoplasmic cellular compartment. A proteolytic cascade conveys the OMP signal by regulated proteolysis of RseA, a membrane-spanning anti-sigma factor whose cytoplasmic domain inhibits sigma(E)-dependent transcription. Upon activation by OMP C termini, the membrane localized DegS protease cleaves RseA in its periplasmic domain, the membrane-embedded protease RseP (YaeL) cleaves RseA near the inner membrane, and the released cytoplasmic RseA fragment is further degraded. Initiation of RseA degradation by activated DegS makes the system sensitive to a wide range of OMP concentrations and unresponsive to variations in the levels of DegS and RseP proteases. These features rely on the inability of RseP to cleave intact RseA. In the present report, we demonstrate that RseB, which binds to the periplasmic face of RseA, and DegS each independently inhibits RseP cleavage of intact RseA. Thus, the function of RseB, widely conserved among bacteria using the sigma(E) pathway, and the second role of DegS (in addition to RseA proteolysis initiation) is to improve the performance characteristics of this signal transduction system.
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http://dx.doi.org/10.1101/gad.1238604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC525548PMC
November 2004

Regulation of the alternative sigma factor sigma(E) during initiation, adaptation, and shutoff of the extracytoplasmic heat shock response in Escherichia coli.

J Bacteriol 2003 Apr;185(8):2512-9

Department of Stomatology, University of California, San Francisco 94143-0512, USA.

The alternative sigma factor sigma(E) is activated in response to stress in the extracytoplasmic compartment of Escherichia coli. Here we show that sigma(E) activity increases upon initiation of the stress response by a shift to an elevated temperature (43 degrees C) and remains at that level for the duration of the stress. When the stress is removed by a temperature downshift, sigma(E) activity is strongly repressed and then slowly returns to levels seen in unstressed cells. We provide evidence that information about the state of the cell envelope is communicated to sigma(E) primarily through the regulated proteolysis of the inner membrane anti-sigma factor RseA, as the degradation rate of RseA is correlated with the changes in sigma(E) activity throughout the stress response. However, the relationship between sigma(E) activity and the rate of degradation of RseA is complex, indicating that other factors may cooperate with RseA and serve to fine-tune the response.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC152616PMC
http://dx.doi.org/10.1128/jb.185.8.2512-2519.2003DOI Listing
April 2003