Cellular interactions and immune cell dynamics within immunological niches

The immune system is composed of large repertoire of B cells, the precursors of antibody forming cells. Each express a unique antibody with different affinity and specificity. We examine how selection of B cells from the pre-vaccinated repertoire are selected for entry into the antibody immune response for differentiation into germinal center cells as well as antibody forming cells. For this we use multiple approaches wherein we examine interactions and niche formation of the immune cells by light sheet fluorescence microscopy and intravital two photon microscopy. Using these methods, we visualize and study the antibody immune response in a whole lymphoid organ at the single cell resolution and visualize entry and exit of B cells from the antibody immune response .

Mucosal vaccinations

We study how antibody forming cells entry respond to antigen delivered through the gut mucosa. As opposed to conventional vaccinations such as intra-dermal or intra-muscular, very little is known about selection of B cells for germinal entry and affinity maturation in the intestinal track. Establishing immunity by oral delivery of immunogen is a very challenging process as the vaccine-specific B cells have to outcompete B cells that are specific for immense amount of gut-derived antigens. We aim to understand whether similar or different set of rules and regulation govern entry into immune response in the gut when compared to the lymph node.

In addition, we examine nasal vaccinations wherein antigen is delivered via the airways. This type of vaccine is used to deliver flu antigens by using aerosol sprays. Very little is known about how these vaccines work and how do the responding cells are distributed in different niches. Understanding this process may lead to improvement of nasal vaccination against influenza and other viral pathogens.

Tumor infiltrating B lymphocytes and anti-tumor antibody discovery

We aim to implement our vast knowledge about B cell immune responses in mice for understanding the function of tumor infiltrating B cells in human cancer. Ovarian and pancreatic cancers rank among the five deadliest types of cancers. Their lack of effective screening strategies and their poor prognoses constitutes an urgent need for the discovery of novel means for early detection and therapy. Immunotherapeutic approaches in oncology underscores the pivotal role of the immune system in the treatment of cancer. Anti-tumor antibodies are one of the safest and efficient therapies available for treatment of cancer patients and in the last decade many antibodies were approved for clinical use. These antibodies are limited so far to rare antigens and to small types of cancer. Thus, there is a great need for discovery of new anti-tumor antibodies.  The development of therapeutic antibodies requires a deep understanding of the interplay between the immune system and cancer cells. We have developed a screening strategy to detect auto-antibodies in the malignant ascites fluids derived from cancer patients. This strategy was employed in order to generate a potential “target bank” for testing future cloned antibodies.

Control of plasma cell formation by chromatin remodelers and post transcriptional RNA regulation

Over the course of differentiation into antibody-forming plasma cells that secrete vast amounts of antibodies over a long period of time, B lymphocytes undergo dramatic transcriptional changes. The B lymphocyte to plasma cell transformation depends on chromatin landscape changes; however, the mechanism by which specific chromatin remodelers facilitate and maintain the commitment to the plasma cell lineage is unknown. To address this problem, we combine a series of new, informative animal models with advanced mechanistic analyses of chromatin modulator functions. Specifically, we focus on the role of the mammalian ATP-dependent chromatin remodeling complexes in B cell differentiation into antibody-forming cells in vivo. We dissect the mechanism of each chromatin remodeler by defining the subunit and associated factor composition and chromatin targeting of each complex over the course of differentiation. We plan to examine these mechanistic findings in healthy and malignant human B cells.