Exploring the mechanisms of primary antibody responses to T cell-dependent antigens.

We have developed a model of the early events that occur during a primary antibody response to a T cell-dependent antigen. Within secondary lymphoid organs, B cell proliferation in response to antigen injection gives rise to two kinds of transient structures: foci that develop in the T cell area, and germinal centers, that develop in the secondary follicles of the B cell area. Foci give rise to plasma cells that are responsible for the majority of early circulating antibody, whereas germinal centers are sites of somatic mutation and memory cell formation. Here we model the cell-cell interactions and cell population kinetics involved in the generation of antibody-forming cell foci, and compare our model with experimental data. We focus on fundamental issues involving the control of B cell proliferation and differentiation, using simple kinetic models that depend on direct cell-cell interactions and on the action of cytokines. We show that with realistic parameter assumptions our model can account for both the rapid cellular expansion and the differentiation of B cells into antibody-secreting cells. By summing the expected antibody production of all the plasmablasts and plasma cells that are generated during the focus response we can account for much of the antibody observed in the serum of mice during a primary response. Lastly, we compare the predictions of our model for two different scenarios for the control of B cell proliferation. In one model, we assume that B cells, once activated, proliferate under the control of cytokines without direct interaction with activated T cells. In the other model, we assume that after dividing B cells return to rest and require a contact-dependent signal from an activated T cell to divide again. The first model gives rise to large foci and antibody levels similar to that observed in experiment, whereas the latter model gives rise to four-fold smaller foci and to circulating antibody levels that are one order of magnitude lower than typical experimental values. This result suggests that B cells may be able to divide without further contact with T cells once a cognate interaction has occurred.