Generation of high affinity antibodies of the appropriate isotype is essential for host defense against extracellular pathogens and for the success of most vaccines. Germinal centers are the sites of both affinity maturation and T cell dependent class switching take. In the previous funding period we performed a series of intravital microscopy studies that revealed novel aspects of germinal center function. We demonstrated that 1) germinal centers are dynamic open structures and that germinal centers B cells migrate between light and dark zones; 2) light and dark zone cells display similar shape size and behavior; 3) naive B cells can migrate through germinal centers; 4) germinal centers can be invaded at any time by higher affinity B cells; 5) plasma blasts display a novel mode of migration in lymph nodes in moving from the follicle to the medullulary cords- a random sprint which is the best way to travel between compartments in a tissue without specific chemotactic cues; 6) that the cyclic reentry model for interzonal migration in germinal centers is correct and that light zone to dark zone migration is controlled by T cell help. In this proposal we propose two new Aims focusing on the role of T cells in controlling early selection events and how follicular helper T cells communicate with germinal center B cells. We hypothesize that 1) affinity based competition between B cells takes place prior to the germinal center reaction; 2) that T cells suppress the emergence of autoreactive B cells and 3) that T cells communicate with B cells through TCR positive microvesicles that are transferred through a dynamic cell-cell junction, or kinapse. We will test these hypotheses through 2 specific Aims: 1) to characterize germinal center affinity competition and T cell mediated regulation of B cell tolerance in the germinal center; and 2) to determine the role of microvesicles in T cell communication with GC B cells in vitro and in vivo. We anticipate that these studies will address the validity of these hypotheses and have an impact on the way that vaccines are designed in the future.
Vaccination is one of the most significant contributions of modern immunology to public health. However, some pathogens including HIV have been very difficult to vaccinate against. The proposed studies will provide new insights into mechanisms operating in germinal centers including somatic mutation that are essential to developing novel vaccination strategies to overcome barriers to host protection.
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