Areas of Interest
Humoral (antibody) Immune Response Initiation Dynamics
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 initiation of the humoral (antibody) immune response.
The humoral immune response is crucial for resistance against viral and bacterial infections. Antibodies are protein molecules that bind to infection-specific, foreign molecular determinants, called antigens (Ag). Upon infection, antigen drains into secondary lymphoid organs that are filled with T and B cells. In lymph nodes (LNs), foreign antigens activate a very small number of B and helper T cells specific for the particular Ag. For a T-dependent humoral response to start, these extremely rare B and helper T cells that migrate in the LNs have to find each other among millions of other lymphocytes in order to form a specific interaction. During these specific interactions activated by antigen B cells get appropriate signals (help) from the respective T cells that enable B cells to proliferate and differentiate into germinal center cells, memory B cells and plasma cells (that secrete antibodies). In my lab we explore whether there are any currently unknown factors that promote/facilitate the interactions between rare activated T and B cells. In addition, we study how various patterns of antigen access to the LNs, the amounts of MHCII/peptide presented by B cells, and T cell TCR affinity for presented MHCII/peptide complex affect the initial interactions between B and T cells, and following it differentiation of B cells. Understanding which of the above parameters play an important role in B cell response may serve to improve the existing vaccination strategies and augment fighting the ongoing infections. We assess which parameters are critical for efficient initiation of humoral responses by combining various experimental and modeling approaches. We use two-photon intravital microscopy (that enables imaging cell migration and interactions in the LNs of living mice) in combination with standard immunological techniques, including flow cytometry and ELISA, to measure the extent of responses on a single cell and organismal level, respectively. Quantitative data obtained by two-photon imaging are then used to build mathematical models of activated T and B cell migration and interaction in lymphoid organs.
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.
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 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.
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.
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)
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.
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.