High affinity, long lasting antibodies and memory B cells provide protection from foreign pathogens and their generation has been the target of nearly all succesful vaccines to date. Their development requires that B cells participate in the T-dependent humoral response and form Germinal Centers (GCs) where B cell affinity maturation and differentiation of long-lived antibody-secreting cells and high-affinity memory B cells takes place. The T-dependent humoral response must be tightly regulated because of its potential to recruit or generate B cells with self-reactivity that can lead to the development of autoimmune diseases. While it is well known that follicular helper and follicular regulatory T cells (Tfh and Tfr) are required for the control of GC responses and Tfh cells are widely studied, the mechanisms of Tfr cell action on newly recruited activated B cells and GC B cells are not fully understood. In my thesis work I found that follicular regulatory T cells can respond to the proinflammatory cytokines CCL3 and CCL4 (which can be secreted by GC B cells) ex vivo and make more frequent interactions with wild-type (WT) than CCL3-deficient GC B cells in vivo. Moreover, I showed that B cell intrinsic production of CCL3 is required for control of GC B cell expansion and is important for limiting the development of antinuclear antibodies. Together, our data suggests that CCL3 secreted by GC B cells promotes their direct interactions and control by Tfr cells in vivo. In addition to analysis of the cellular and molecular mechanisms of Tfr action on GC B cells, we also examined how kinetics of Tfh and Tfr cell response affects the recruitment of newly arriving antigen-specific B cells into the GC response. We found that B cells have a short, limited time frame in which they can participate in ongoing immune responses. Preloading B cells with activating antigen alone is sufficient to promote their participation at all stages of the GCs despite differences in the number and quality of follicular T cells. Our data suggests that antigen-triggered activation may be the limiting factor for continuous recruitment of antigen-specific B cells into immunization-induced response. Overall, the findings of this work may be important for future improvements of vaccination approaches against pathogenic diseases and better treatments or prevention of autoimmune diseases.
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Control of B Cell Participation in the T-dependent Humoral Immune Response by Follicular Regulatory T Cells and Other Factors