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  • It is interesting to note that Eibinger

    2020-01-11

    It is interesting to note that Eibinger and colleagues [23] recently reported chemotactic movement to 25-OHC in THP1 cells as well as in primary human monocytes. RNA interference suggested that in part this migration was mediated by EBI2.
    Competing financial interest statement
    Acknowledgments
    Introduction Affinity maturation of B cells in the germinal center (GC) is a process of evolution involving mutation of B cell receptors (BCRs) followed by selection through antigens and T cells (Victora and Nussenzweig, 2012). Consequently, an important GC function is to make the most effective Sunitinib possible, thereby providing efficient immune protection. GCs are tightly confined clusters of cells within the follicle, in which GC B cells highly express the transcription factor Bcl6 and the G-protein-coupled receptor sphingosine-1-phosphate receptor (S1pr2) that promotes their retention within the GC structure (Green et al., 2011, Huang and Melnick, 2015). In GCs, B cells migrate between two zones, the light zone (LZ) and the dark zone (DZ), and in the latter, they proliferate and hypermutate their BCRs (Victora et al., 2010). In the LZ, antigen-presenting follicular dendritic cells and T follicular helper (Tfh) cells reside, and here, GC B cells expressing newly mutated BCRs capture antigen and internalize it for presentation to T cells (De Silva and Klein, 2015). Subsequently, antigen- and T cell-dependent selection occurs, whereby positively selected GC B cells have the “choice” of recycling to the DZ for further mutation or exiting the GC as memory cells or plasmablasts (Shinnakasu and Kurosaki, 2017, Suan et al., 2017). For plasma cell differentiation, BCRs in post-GC plasma cells are heavily dominated with a high-affinity mutation, even at a time point when this mutation is present in only a small fraction of GC cells (Phan et al., 2006). Hence, higher-affinity cells are directed to the plasma cell fate, whereas lower-affinity cells enter into the recycling GC cell pool. In regard to the selection mechanism, it has been postulated that precursor cells (selected toward recycling GC or plasma cell fates) become committed already in the GCs (Suan et al., 2017, Victora and Nussenzweig, 2012), thereafter entering the recycling DZ or plasmablast pool, respectively. Indeed, it has been suggested that a small fraction of LZ GC cells expressing c-Myc, a key cell-cycle regulator, correspond to such precursor cells; c-Myc+ cells are enriched for high-affinity BCRs, and ablation of Myc affects DZ reentry (Calado et al., 2012, Dominguez-Sola et al., 2012). But, assuming that distinctive precursors for GC recycling or plasma cell fates exist, it is unclear whether both precursors or Sunitinib only GC recycling precursors express c-Myc. It was also reported that IRF4, a key factor for initiating plasma cell differentiation, is expressed in a small subset of mouse LZ GC B cells (De Silva et al., 2016). However, the published data show that these IRF4+ cells do not express Bcl6. Considering the recent evidence that early plasmablasts reside in the GC LZ region (Kräutler et al., 2017), the observed IRF4+ cells are more likely early plasmablasts rather than bona fide GC B cells. Thus, the model of precursors in the GC for fate decisions still remains speculative. Here, to test this model and, if correct, to address how such precursor GC cells are formed, we first identified a small LZ GC cell population (Bcl6loCD69hi) with higher-affinity BCRs that expresses IRF4 and favors the plasma cell fate over GC recycling. In contrast, Bcl6hiCD69hi LZ GC cells with lower-affinity favored GC recycling, The Bcl6loCD69hi population has begun to downregulate Bcl6 and S1pr2 and to upregulate Gpr183, which likely represents the process of restraining the GC program and of exiting the GC. Mechanistically, Bcl6loCD69hi cell formation relied on CD40 in a dose-dependent manner. Furthermore, we found that expression of intercellular adhesion molecule 1 (ICAM-1) and signaling lymphocytic activation molecule (SLAM) in LZ GC cells was upregulated by CD40 stimulation. Consequently, Bcl6loCD69hi cells expressed these adhesion molecules higher than Bcl6hiCD69hi cells, thereby affording more stable GC B-Tfh cell contacts; attenuating this interaction decreased expression of IRF4. Thus, we propose a precursor model in which the duration of Tfh-GC B cell interactions is a key decisive factor for formation of plasma cell precursor versus GC recycling precursor cells.