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  • From a mechanistic standpoint the BCL

    2019-08-01

    From a mechanistic standpoint, the BCL6 RD2 domain represses the GPR183 and S1PR1 loci by recruiting HDAC2, but not MTA3-NuRD, to suppress the enhancer activation mark H3K27ac at their distal regulatory elements. However, these data do not exclude the possibility that other as yet unknown corepressor proteins may bind with BCL6-HDAC2 repression complexes to these key target genes. Taken together with recent findings showing that BCL6 BTB domain corepressors distribute to different sets of genomic loci with unique functions in GC Clobetasol propionate (Hatzi et al., 2013), these data suggest that transcriptional programming by BCL6 is exquisitely compartmentalized through linkage of distinct biochemical functions to genes involved in specific immunological and biological functions. In contrast to Bcl6−/− T cells, Bcl6RD2MUT T cells were partially impaired in their ability to form GC-TFH cells (Figure S6), which is somewhat similar to a hypomorphic defect observed in Bcl6 T cells (Yu et al., 2009). This defect is partially explained by the fact that RD2 mutant GC-TFH cells exhibited reduced IL-21 expression and increased Blimp1. Repression of Blimp1 by BCL6 is known to critical for GC-TFH cell differentiation and function (Johnston et al., 2009). IL-21 is expressed by GC-TFH cell to promote GC B cell development and maintenance (Linterman et al., 2010, Zotos et al., 2010). Unlike Bcl6−/− mice, inflammatory responses and macrophage regulation were not significantly disrupted in Bcl6RD2MUT mice. Neither loss of the BTB domain lateral groove nor the RD2 domain are sufficient to elicit deregulation of inflammatory signaling, which must instead be more reliant on other functions of Bcl6. The dominant mechanism may be linked at least in part to the previously reported competition with STAT proteins for binding to promoters of genes regulating inflammatory signaling (Dent et al., 1997, Huang et al., 2013) (Figure S6).
    Experimental Procedures
    Author Contributions
    Acknowledgments A.M. is supported by NCI R01 104348 and is also supported by the Burroughs Wellcome Foundation and Chemotherapy Foundation. A.H. and D.G.G. are supported by NIH grants R01AI080850 and R21AI101704. This research was initially supported by a March of Dimes Basil O’Connor Scholar Award (A.M.). This work was facilitated by the Sackler Center for Biomedical and Physical Sciences at Weill Cornell Medical College. We thank H. Ye from the Albert Einstein College of Medicine for sharing Bcl6 mice and P. Wade from NIH for providing anti-MTA3.
    EBI2 and its ligand(s) EBI2 was found in a screen of upregulated genes in human B cells upon infection with EBV [1]. EBI2 is a G-protein (Gαi type) coupled receptor [2] but as long as 18 years after its discovery the nature of its ligand remained undisclosed. With the help of transfected cell lines and EBI2 knockout animals, researcher from Novartis and J&J independently from each other discovered the ligands from extracts of sheep liver and porcine spleen respectively [3,4]. The description of the natural ligands of EBI2 advanced the understanding of the biology of the receptor enormously and led to the fast development of potent antagonists [5,6]. Both groups found 7α,25-OHC to be the most potent ligand in signaling and in induction of migration of transfected and primary immune cells. The second best ligand was 7α,27-OHC whereas 25-OHC showed only a minor residual activity [3,4]. Importantly, usage of cells from EBI2 deficient mice showed that the action of the ligands via EBI2 are non-redundant. Similarly, knockout of one of the major enzymes generating the ligand from cholesterol, CH25H, showed very similar phenotypes in terms of B cell localization in germinal centers as the EBI2 knockout mouse [3] (see below), proving that indeed these dihydroxycholesterols are the physiological relevant ligands of EBI2.
    Role of EBI2 in the immune system Even before the ligand was characterized, several high impact papers showed an important role of EBI2 in the germinal center reaction and B cell maturation, which is crucial for fast high affinity antibody production against foreign invaders [7,8]. After definition of the ligands, the cells expressing the ligand-generating enzymes were deciphered. It was shown that in lymphoid tissues so called lymphoid stromal cells express CH25H and CYP7B1 and the ligand degenerating enzyme HSD3B7 in a coordinated manner to localize B cells at the follicle perimeter. At this site at the border of the T cell zone, B cells receive T cell help for efficient antibody production [9].