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    • Although CCR expression clearly identifies MBC

    2021-05-07

    Although CCR6 expression clearly identifies MBC precursors within the GC, we found that the expression of this chemokine receptor by responding antimalaria medication was not required for MBC differentiation and had no detectable impact on the GC subsets analyzed in this study. Although this is in agreement with studies of mice challenged with phycoerythrin (Elgueta et al., 2015), other studies employing the NP-KLH immunogen have noted some increase in GC size (Wiede et al., 2013) and a shift in the LZ/DZ ratio (Reimer et al., 2017) in CCR6-deficient mice, potentially linked to CCR6 function early in the response. Although these effects could also be due to CCR6 functions in non-B cells or subtle differences associated with different immunization strategies, all of these studies are consistent in showing that CCR6 is not required for MBC development despite the important role it does play in MBC positioning and subsequent function during recall responses (Elgueta et al., 2015). The mRNA microarray data derived from human tonsillar B cell populations provide strong evidence that CCR6+ LZ B cells form the precursors for MBCs in both human and mouse GCs. In addition, the specific transcripts differentially regulated during the process of MBC differentiation could provide insights into MBC differentiation and function. CCR6+ MBC precursors in the LZ were found to increase S1PR1 and decrease S1PR2, potentially facilitating egress from the GC (Green and Cyster, 2012). Similarly, EBI2 (GPR183) was increased, consistent with surface expression of EBI2 in our murine experiments, which could facilitate migration of MBCs toward the outer follicle (Gatto and Brink, 2013). The expression of S1PR1, EBI2, and CCR6 therefore follows a similar pattern: undergoing marked reduction upon GC B cell differentiation and a subsequent increase upon commitment to MBC differentiation. Because the loss of S1PR1 and EBI2 expression on GC B cells is due to direct BCL6-mediated suppression of S1pr1 and Gpr183 (Huang et al., 2014) and Ccr6 possesses a functional BCL6-binding site (Hatzi et al., 2015), it is likely that the coordinated repression of these homing receptor genes in GC B cells and their subsequent re-expression upon MBC differentiation are attributable to the enforcement and subsequent release of BCL6-mediated transcriptional repression, respectively. This scenario is consistent with the concept that MBC differentiation in the GC is associated with reduced antigen and/or Tfh cell inputs, leading to the loss of the GC B cell transcriptional signature largely through the activity of BCL6. Unlike plasma cell differentiation, however, loss of BCL6 during MBC differentiation is not accompanied by the induction of IRF4 and BLIMP1 because it requires engagement of high-affinity antigen by the BCR (Kräutler et al., 2017). Two recent studies used specialized reporter mice to identify GC B cells with either decreased expression of S1pr2 (Laidlaw et al., 2017) or cell-cycle quiescence (Wang et al., 2017). Because the cells identified in each of these studies were also enriched with Ccr6 transcripts (Laidlaw et al., 2017, Wang et al., 2017), it is likely that they are closely related to the LZ-resident MBC precursors that we report here. Nevertheless, the ability to utilize surface staining for CCR6 provides a unique and universal method for identifying MBC precursors in both mice and humans without the requirement of specialized reporter systems. In this regard, it is important to emphasize that a definitive GC B cell gate (such as those described in this study) is required in conjunction with CCR6 detection to ensure that cells that have already undergone full MBC differentiation are excluded from any population defined as MBC precursors by flow cytometry. For instance, the mouse MBC precursors recently identified by Wang et al. (2017) expressed high levels of CD38 but would have been mostly excluded by the flow-cytometric gates used in our study. Determining how much CD38 is in fact expressed on MBC precursors within mouse GCs will ultimately require coupled photo-conversion and flow-cytometry studies, but it is reasonable to postulate that the CCR6+CD38lo LZ B cells we have described are the earliest cells identifiably committed to MBC differentiation within mouse GCs. Similarly, the human GC B cell gates employed in our study also enabled the identification of CCR6+ LZ cells that had only recently committed to MBC differentiation, as evidenced by the fact that they retained expression of BCL6 mRNA.