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Chromosomal rearrangements in non-Hodgkin's B-cell lymphoma implicate BCL-6 as an oncogene, yet direct evidence for BCL-6 acting as an oncogene in B cells has been lacking. Here, we show that BCL-6 can immortalize primary B cells, but only in the absence of p53 tumor suppressor function. The expression of BCL-6 led to greatly increased B-cell proliferation, particularly in response to CD40 stimulation. Furthermore, BCL-6-infected p53-deficient B cells gave rise to immortalized cell lines that could be maintained by CD40 stimulation. We found that in primary mouse B cells, BCL-6 repressed expression of the Blimp-1, p27kip1, and cyclin D2 target genes. BCL-6 did not markedly repress the PDCD2 and BCL-XL target genes. The BCL-6 immortalized cell lines had a phenotype consistent with germinal center B cells, they expressed the germinal center-specific M17 gene, and a significant fraction of the cells stained positive with PNA. Our data indicate that BCL-6 may act to maintain B cells in a germinal center-like state, and repression of Blimp-1 by BCL-6 may be particularly crucial for stabilization of the germinal center phenotype. Our data also suggest that disruption of the p53 pathway may be crucial for the development of BCL-6-expressing B-cell lymphomas.Oncogene (2004) 23, 839-844. doi:10.1038/sj.onc.1207065 [ABSTRACT FROM AUTHOR]

The transcriptional repressor protein BCL-6, implicated in the pathogenesis of B cell lymphoma, regulates lymphocyte differentiation and inflammation. We investigated the mechanism for the T helper cell subset 2 (TH2)-type inflammation that occurs in BCL-6-/- mice. Using chimeric mice we found that the TH2-type inflammation is dependent upon nonlymphoid cells. We identified three chemokines, MCP-1, MCP-3 and MRP-1, which are negatively regulated by BCL-6 in macrophages. Promoter analysis revealed that BCL-6 is a potent repressor of MCP-1 transcription. Our results provide a mechanism for the regulation of TH2-type inflammation by BCL-6 and link TH2 differentiation to innate immunity. [ABSTRACT FROM AUTHOR]

Many autoimmune diseases are characterized by the production of autoantibodies. The current view is that CD4+ T follicular helper (Tfh) cells are the main subset regulating autoreactive B cells. Here we report a CXCR5+PD1+ Tfh subset of CD8+ T cells whose development and function are negatively modulated by Stat5. These CD8+ Tfh cells regulate the germinal center B cell response and control autoantibody production, as deficiency of Stat5 in CD8 T cells leads to an increase of CD8+ Tfh cells, resulting in the breakdown of B cell tolerance and concomitant autoantibody production. CD8+ Tfh cells share similar gene signatures with CD4+ Tfh, and require CD40L/CD40 and TCR/MHCI interactions to deliver help to B cells. Our study thus highlights the diversity of follicular T cell subsets that contribute to the breakdown of B-cell tolerance. B cell response and antibody production are generally facilitated by CD4+ follicular helper (Tfh) cells. Here the authors identify a subset of CXCR5+PD1+CD8+ Tfh cells that is normally suppressed by STAT5 signaling, so that STAT5 deficiency in mice increases the number of these CD8+ Tfh cells and induces concomitant production of autoantibodies. [ABSTRACT FROM AUTHOR]