Areas of Interest
Spatio-temporal dynamic regulation of T-dependent B cell immune response in health and disease.
The mammalian immune system has evolved to respond to a variety of infectious agents by integrating "danger signals" into distinct signaling outcomes and thus distinct dynamics of intercellular interactions. When the immune response is successful, disease eradication occurs. Our research interests are directed at understanding the quantitative principles that underlie this "signal processing" in an adaptive immune response, specifically in the T-dependent B cell response.
Proper regulation of T-dependent B cell responses is critical for our ability to generate long-term high affinity antibodies (Abs) against multiple pathogens. At the same time, disregulation of B cell responses can lead to development of autoimmunity and cancer. T-dependent immune response is a complex multistep process, where acquisition of antigen and T cell help may lead to B cell activation and differentiation into short-lived antibody-secreting plasma cells (PCs) and/or germinal center (GC) B cells that in turn may give rise to high-affinity long-lived memory B cells and PCs. The goal of our research is to understand various factors that affect 1) B cell recruitment into T-dependent response, 2) B cell selection in GCs into long-lived memory B cells and PCs, 3) control of self-reactive B cells, and to assess their role in vaccines, autoimmune disorders and B cell lymphomas. In the lab we utilize a combination of standard immunological methods, confocal and two-photon intravital microscopy (that enables imaging cell migration and interactions in the lymph nodes of living mice) and systems biology approaches.
Irina L. Grigorova, Rachna Chaba, Hong Ji Zhong, Benjamin M. Alba, Virgil Rhodius, Christophe Herman, and Carol A. Gross, 2004. Fine-tuning of the Escherichia coli sigma E envelope stress response relies on multiple mechanisms to inhibit signal-independent proteolysis of the transmembrane anti-sigma factor, RseA. Genes Dev, Vol. 18, pp2686-2697.
Irina L Grigorova, Naum J. Phleger, Vivek K. Mutalik, Carol Gross, 2006. Insights into transcription regulation by Es recruitment to promoters and s's competition from an equilibrium model of RNA polymerase binding to DNA. PNAS. Vol. 103(14):5332-7.
Phan TG, Grigorova I, Okada T, Cyster JG, 2007 Subcapsular encounter and complement-dependent transport of immune complexes by lymph node B cells. Nat Immunol. Sep;8(9):992-1000.
Chaba R*, Grigorova IL*, Flynn JM, Baker TA, Gross CA, 2007. 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. Jan 1;21(1):124-36. (* co-first authors)
Woolf E, Grigorova I, Sagiv A, Grabovsky V, Feigelson SW, Shulman Z, Hartmann T, Sixt M, Cyster JG, Alon R, 2007. Lymph node chemokines promote sustained T lymphocyte motility without triggering stable integrin adhesiveness in the absence of shear forces. Nat Immunol. Oct;8(10):1076-85.
Grigorova IL, Schwab SR, Phan TG, Pham TH, Okada T, Cyster JG, 2009. Cortical sinus probing, S1P1-dependent entry and flow-based capture of egressing T cells. Nat Immunol. Jan;10(1):58-65.
Suzuki K, Grigorova I, Phan TG, Kelly L, Cyster JG, 2009. Visualizing B cell capture of cognate antigen from follicular dendritic cells. J Exp Med, 2009 Jun 8.
Grigorova I, Panteleev M, Cyster JG. Lymph node cortical sinus organization and relationship to lymphocyte egress dynamics and antigen exposure. Accepted to publication by PNAS 2010 Sep.
Arnon TI, Horton RM, Grigorova IL, Cyster JG. Visualization of splenic marginal zone B-cell shuttling and follicular B-cell egress. Nature. 2013 Jan 31;493(7434):684-8.
Turner JS, Marthi M, Benet ZL, Grigorova I. Transiently antigen-primed B cells return to naive-like state in absence of T-cell help. Nat Commun. 2017 Apr 21;8:15072.
Turner JS, Benet ZL, Grigorova IL. Antigen Acquisition Enables Newly Arriving B Cells To Enter Ongoing Immunization-Induced Germinal Centers. J Immunol. 2017 Aug 15;199(4):1301-1307.
Turner JS, Benet ZL, Grigorova I. Transiently antigen primed B cells can generate multiple subsets of memory cells. PLoS One. 2017 Aug 29;12(8):e0183877.
Wolf SJ, Theros J, Reed TJ, Liu J, Grigorova IL, Martínez-Colón G, Jacob CO, Hodgin JB, Kahlenberg JM. TLR7-Mediated Lupus Nephritis Is Independent of Type I IFN Signaling. J Immunol. 2018 Jul 15;201(2):393-405.
Benet ZL, Marthi M, Ke F, Wu R, Turner JS, Gabayre JB, Ivanitskiy MI, Sethi SS, Grigorova IL. CCL3 Promotes Germinal Center B Cells Sampling by Follicular Regulatory T Cells in Murine Lymph Nodes. Front Immunol. 2018 Sep 13;9:2044. doi: 10.3389/fimmu.2018.02044. eCollection 2018.
Turner JS, Ke F, Grigorova IL. B Cell Receptor Crosslinking Augments Germinal Center B Cell Selection when T Cell Help Is Limiting. Cell Rep. 2018 Nov 6;25(6):1395-1403.e4. doi: 10.1016/j.celrep.2018.10.042.