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  • br Results br Discussion It has

    2020-05-19


    Results
    Discussion It has been thought that commitment to the plasma cell fate begins while pd 0332991 are still in the GC (Suan et al., 2017, Victora and Nussenzweig, 2012), but the main obstacle to test this model and, if correct, to clarify how the plasma cell-prone GC cells develop has been our inability to identify such cells. By using Bcl6 reporter mice, we were able to identify a small population of LZ GC B cells (Bcl6loCD69hi) with higher BCR affinity than other identified GC subpopulations. These Bcl6loCD69hi cells were preferentially committed to the plasma cell fate rather than to recycling in the GC. Mechanistically, we found that CD40 acted as a dose-dependent regulator of Bcl6loCD69hi cell formation. Based on the asymmetric distribution of Bcl6 and the IL-21 receptor in GC cells, an asymmetric B cell division model for subsequent GC recycling and plasma cell fate decisions has been proposed (Barnett et al., 2012). In this regard, Bcl6loCD69hi cells might represent the progeny of asymmetric division, leading to their lower expression of Bcl6. However, the expression of IL-21 receptor was similar between Bcl6loCD69hi and Bcl6hiCD69hi cells (data not shown). Thus, as originally proposed, the asymmetric model for post-GC fate decisions seems not to operate in our experimental settings. Apart from T cell help, the requirement for BCR signaling in GC fate decisions has been investigated (Kräutler et al., 2017). It has become clear that signals provided by the BCR and T cell help interact and participate in the plasma cell fate decision during GC reactions. Among the various components of Tfh cell help, the role of CD40 in recycling GC versus plasma cell fates has been controversial. Previous experiments using direct stimulation of CD40 or loading of GC B cells with extrinsic peptides led to different conclusions. Although both approaches lead to a dramatic increase in post-GC plasma cell fate, direct stimulation of CD40 (Erickson et al., 2002, Kishi et al., 2010), but not stimulation with extrinsic peptide (Victora et al., 2010), curtailed the GC reaction. Our finding that decision between plasma cell and GC recycling fates is dependent on CD40 in a dose-dependent manner could reconcile these previous observations. In contrast to strong supra-physiological and monotonous CD40 signaling, which generates only plasmablasts, stimulation by extrinsic peptide could generate a broader range of T cell help. Indeed, the extent of GC proliferation in these extrinsic peptide experiments could be altered, depending upon the dose of the injected peptide (Gitlin et al., 2014); therefore, these GC B cells could take both plasma cell and GC recycling fates. Our genetic evidence for the CD40 requirement in post-GC plasma cell differentiation seems to be inconsistent with results from a recent study demonstrating apparently normal generation of early plasma cells after anti-CD40L blocking in hen egg lysozyme (HEL)-conjugated sheep-red blood cell (RBC)-immunized mice (Kräutler et al., 2017). Given that virus-like particle immunization induces GC B cells as well as IgG+ memory B cells independently of T cell help to some extent (Liao et al., 2017), one straightforward interpretation is that the sheep RBC immunization model induces plasma cell responses with a less stringent T cell requirement. BCR affinity serves as a determinant of the amount of peptide-MHC II (pMHC) presented on the GC cell surface; GC B cells with higher pMHC densities compete favorably for access to Tfh cells (Victora et al., 2010). Also, this more intense pMHC interaction induces inside-out signaling by cognate Tfh cells to activate integrins (Burbach et al., 2007) as well as to externalize CD40L from intracellular stores, making it more available for cognate GC B cells (Liu et al., 2015). As a potential mechanism connecting CD40 signal strength, GC B-Tfh cell contact, and post-GC plasma cell fates, we propose a model based on the following three lines of evidence, in which strong CD40 signaling facilitates stable GC B-Tfh cell interactions, thereby contributing to development of Bcl6loCD69hi plasma cell-prone GC cells. First, CD40L stimulation of LZ GC B cells enhances expression of ICAM-1, SLAM, and CD40 on GC B cells as well as their stable association with Tfh cells. In addition, a feed-forward loop is formed in which stable GC B-Tfh cell interactions further enhance CD40 signaling, because anti-ICAM-1 treatment blocks CD40-mediated IRF4 induction. Second, in vivo, well correlated with highest expression of ICAM-1, SLAM, and CD40 on Bcl6loCD69hi plasma cell-prone GC B cells, these cells manifest the most stable association with Tfh cells, compared with other LZ GC fractions. Finally, in vivo anti-ICAM-1 treatment inhibits development of Bcl6loCD69hi cells.