Regulation of germinal center response by proinflammatory chemokine CCL3 and follicular regulatory T cells

Abstract

Abstract Follicular regulatory T cells (Tfrs) have been reported to play multiple roles in the control of B cell responses. Tfr repress foreign antigen-specific B cells and plasma cells at the peak of germinal center (GC) response. At the same time they promote GC B cell cycling in IL10-dependent fashion and support optimal affinity maturation. Ex vivo Tfrs can act directly on both Tfh and GC B cells. However, relative contribution of direct Tfr-mediated control of Tfh cells vs GC B cells in vivo has been unclear. Our previous work suggested that GC B cell-intrinsic production of proinflammatory chemokine CCL3 promoted direct GC B cell contacts with Tfr cells and was important for modest negative regulation of B cells at the peak of GC response. In this follow up study we have addressed the role of CCL3 in the long-term regulation of GCs. We have also assessed, which subset of GC B cells upregulates production of CCL3 and which receptors on Tfr cells may respond to this chemokine. We found that in addition to the role of CCL3 in the modest repression of foreign antigen-specific B cells at the peak of GC response, it was also important for longer-term participation of B cells in GCs. Both the negative and positive regulation of GC B cells by CCL3 was dependent on the presence of Tregs. We also found that only about 10% of GC centrocytes that were Myc-positive upregulated expression of CCL3 and that Tfr chemotaxis to CCL3 chemokine ex vivo was dependent on both CCR5 and CCR1 chemokine receptors. Further studies are underway to determine the role of Tfr cells in the negative and positive CCL3-mediated regulation of GCs.