Cellular and Molecular Immunology
B cells and T cells in health and disease.
B and T lymphocytes are crucial for protective immune responses against infectious diseases and cancer but may also cause autoimmune diseases. B and T cells recognize infectious antigens or cancer antigens by use of highly specific receptors. It is well established that B and T cells mutually stimulate each other (collaborate) by joint recognition of the same antigen. The mechanism appears to be that while the B cell receptors recognize antigen in the extracellular fluid, T cells recognize fragments of the antigen bound to Major Histocompatibility Complex (MHC) molecules on the B cell surface.
Our studies have added to this picture: the B cell receptors, immunoglobulins, are themselves partially degraded and short fragments derived from the Variable regions are presented on MHC molecules to T cells (Weiss and Bogen, PNAS-89, Cell-91). By this mechanism B cells can themselves present their unique V-regions (idiotopes, Id) to T cells, a phenomenon that forms the basis for a novel type of Id-dependent T-B collaboration (Munthe et al J Immunol 2004). Excessive Id-dependent T-B collaboration appears to cause production of autoantibodies and autoimmune disease (Munthe et al. J Immunol 2005, Zangani et al Am J Pathol 2009). The mechanism is that self reactive B cells receive help from Id-specific T cells, thereby circumventing a lack of conventional T cell help (due to T cell tolerance for self antigen). Id-driven T-B collaboration can, when chronic, induce B cell lymphomas (Zangani et al., J Exp Med 2007).
In another direction of research, we have shown that Id-specific T cells can also kill multiple myeloma cells (Dembic et. al. PNAS 2000, Blood 2001) and B lymphoma cells (Lundin et al., Blood 2003). In this case monoclonal immunoglobulins abundantly secreted by the tumor cells are picked up and presented by MHC molecules on professional antigen presenting cells like dendritic cells infiltrating the cancer tissue. This results in activation of Id-specific T cells and an indirect killing of myeloma cells (Corthay et al. Immunity 2005, Corthay et al. Cancer Res 2009).
In yet another direction of research, we are deveoping novel vaccines based on the findings that fragments of antibodies are presented on MHC molecules. Thus, we develop recombinant immunoglobulin-based vaccines that target genetically integrated antigen to antigen presenting cells (APC) that initiate immune responses. A first generation of vaccines, called Troybodies (Lunde et. al., Nat Biotech 1999, Rasmussen et al PNAS 2001, Flobakk et al J Immunol 2008), only have the ability to stimulate T cell responses. A second generation of vaccines, called Vaccibodies, can stimulate both B and T cell responses (Fredriksen et al, Blood 2007, Schjetne et al. J Immunol 2007). These Ig-based vaccines are genetically equipped with V-regions that target them to receptors of the innate immune system for induction of potent immune responses. They are delivered as DNA vaccines. Recent experiments have given very promising results since Vaccibody DNA vaccines protect against influenza.