Irina Grigorova, Ph.D.
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 that recirculate through the lymph and blood circulatory system. 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 ~ 106 -107 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 plasma cells (that secrete antibodies) or germinal center cells. Even though activated T cells are proliferating and activated helper T and B cells move to the interface between their resident T and B zones in the LN, it is still unclear whether the timing of the early B cell response could be entirely explained by their random encounters. In my lab we are using a combination of approaches to study the interactions between activated Ag-specific B and T cells. 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. By combining the experimental and modeling approaches, we will explore whether there are any currently unknown factors that could promote/facilitate the interactions between rare activated T and B cells.
Productive interaction between activated T and B cells requires binding of T cell receptor (TCR) to an antigenic peptide presented on the major histocompatibility complex class II (MHCII) molecule of the corresponding B cell. Communication between appropriate T and B cells also depends on the interactions between costimulatory molecules expressed on one of the cells with their corresponding ligands on the other cell (such as CD40L/CD40, OX40/OX40L and ICOSL/ICOS interactions). Molecular details of these interactions and thereby induced intracellular signaling has been studied in vitro. However, how variation in antigen load, TCR affinity and costimulatory molecule/ligand expression affects T/B cell interactions in vivo and the resulting B cell response has not been thoroughly addressed. In my lab we are exploring how antigen levels, timing of B cell exposure to antigen, the amounts of MHCII/peptide presented by B cells, and T cell TCR affinity for presented MHCII/peptide complex affect the initial interactions and differentiation of B cells.
In addition, we will explore how various patterns of antigen access to the LNs affect the early stages of B cell response and which parameters are critical for efficient humoral response initiation. This knowledge could improve existing strategies for vaccine development and lead to development of new ways to augment the immune system to fight ongoing infections.
Research Opportunities for Rotating Students
Grigorova I, Panteleev M, Cyster JG. Lymph node cortical sinus organization and relationship to lymphocyte egress dynamics and antigen exposure. PNAS 107(47): 20447-52, 2010 Nov 23.
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. 206:1485-93.
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. 10:58-65.
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. 8:1076-85.
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. 8:992-1000.