Immunity https://doi.org/10.1016/j.immuni.2021.08.028 (2021)
B cells activated by T cell-dependent antigens converge to form germinal centers (GCs), where they can undergo rounds of diversification and selection by follicular helper T cells (TFH cells) before exiting as plasma cells or memory B cells. TFH cells provide interleukin 4 (IL-4) to GC B cells and thereby amplify the GC response; however, IL-4 is not selectively released into the T cell–B cell synapse, and how IL-4 availability affects GC B cell fate is still unclear. In Immunity, Duan et al. report that follicular dendritic cells (FDCs) residing in the light zone (LZ) of GCs express the receptor IL-4Ra and act to limit the availability of IL-4 to bystander GC B cells that are not directly receiving cognate interactions with TFH cells. Single-cell RNA-sequencing analysis of LZ B cells revealed a subset of IL-4Ra+ B cells that express CD23 but have lower expression of Myc than that of CD23– B cells. These CD23+IL-4Ra+ B cells are poised to become either plasma cells or memory cells, but express lower-affinity antigen receptors and have fewer V(D)J somatic mutations than those of CD23– LZ B cells. Although Il4ra–/– mice have lower overall numbers of LZ CD23+ B cells after immunization, a greater portion of these cells differentiate into memory B cells; conversely, administration of exogenous IL-4 increased the frequency of LZ CD23+ B cells, but decreased the formation of memory B cells, in both wild-type mice and mice deficient in the deaminase AID. Those findings indicate a role for IL-4Ra signaling in restraining the generation of memory B cells. Using a clever antibody-targeting scheme to deliver antigen to congenic mixed–bone marrow chimeric mice, the authors show bystander LZ B cells can nevertheless receive IL-4 signals that influence their fate. As FDCs have abundant expression of IL-4Ra, the authors conditionally deleted Il4ra from this stromal cell population and showed that the generation of memory B cells was decreased in these mice, which had lower antibody responses to secondary immunization, and that affinity selection was also altered in the plasma cell population. Overall, this study shows that FDCs serve crucial roles within the GC microenvironment to restrict the availability of IL-4 to activated GC B cells, such that higher-affinity LZ B cells in direct contact with TFH cells preferentially receive IL-4 signals and continue in their GC fate, whereas the generation of memory cells is not blocked for lower-affinity B cells that have become bystanders in the GC response.
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