Browsing by Subject "Proto-Oncogene Proteins c-bcl-6"

Now showing 1 - 3 of 3
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    Gut microbiota regulates K/BxN autoimmune arthritis through Tfh but not Th17 cells
    (American Association of Immunologists, 2016-02-15) Block, Katharine E.; Zheng, Zhong; Dent, Alexander L.; Kee, Barbara L.; Huang, Haochu; Department of Microbiology & Immunology, IU School of Medicine
    The bacterial community that colonizes mucosal surfaces helps shape the development and function of the immune system. The K/BxN autoimmune arthritis model is dependent on the microbiota, and particularly on segmented filamentous bacteria, for the autoimmune phenotype. The mechanisms of how the gut microbiota affects arthritis development are not well understood. In this study, we investigate the contribution of two T cell subsets, Th17 and follicular helper T (Tfh), to arthritis and how microbiota modulates their differentiation. Using genetic approaches, we demonstrate that IL-17 is dispensable for arthritis. Antibiotic treatment inhibits disease in IL-17-deficient animals, suggesting that the gut microbiota regulates arthritis independent of Th17 cells. In contrast, conditional deletion of Bcl6 in T cells blocks Tfh cell differentiation and arthritis development. Furthermore, Tfh cell differentiation is defective in antibiotic-treated mice. Taken together, we conclude that gut microbiota regulates arthritis through Tfh but not Th17 cells. These findings have implications in our understanding of how environmental factors contribute to the development of autoimmune diseases.
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    IL-21 restricts T follicular regulatory T cell proliferation through Bcl-6 mediated inhibition of responsiveness to IL-2
    (Springer Nature, 2017-03-17) Jandl, Christoph; Liu, Sue M.; Cañete, Pablo F.; Warren, Joanna; Hughes, William E.; Vogelzang, Alexis; Webster, Kylie; Craig, Maria E.; Uzel, Gulbu; Dent, Alexander; Stepensky, Polina; Keller, Bärbel; Warnatz, Klaus; Sprent, Jonathan; King, Cecile; Microbiology and Immunology, School of Medicine
    T follicular regulatory (Tfr) cells control the magnitude and specificity of the germinal centre reaction, but how regulation is contained to ensure generation of high-affinity antibody is unknown. Here we show that this balance is maintained by the reciprocal influence of interleukin (IL)-2 and IL-21. The number of IL-2-dependent FoxP3+ regulatory T cells is increased in the peripheral blood of human patients with loss-of-function mutations in the IL-21 receptor (IL-21R). In mice, IL-21:IL-21R interactions influence the phenotype of T follicular cells, reducing the expression of CXCR4 and inhibiting the expansion of Tfr cells after T-cell-dependent immunization. The negative effect of IL-21 on Tfr cells in mice is cell intrinsic and associated with decreased expression of the high affinity IL-2 receptor (CD25). Bcl-6, expressed in abundance in Tfr cells, inhibits CD25 expression and IL-21-mediated inhibition of CD25 is Bcl-6 dependent. These findings identify a mechanism by which IL-21 reinforces humoral immunity by restricting Tfr cell proliferation.
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    A negative feedback loop mediated by the Bcl6-cullin 3 complex limits Tfh cell differentiation
    (Rockefeller University Press, 2014-06-02) Matthew, Rebecca; Mao, Ai-ping; Chiang, Andrew H.; Bertozzi-Villa, Clara; Bunker, Jeffery J.; Scanlon, Seth T.; McDonald, Benjamin D.; Constantinides, Michael G.; Hollister, Kristin; Singer, Jeffrey D.; Dent, Alexander L.; Dinner, Aaron R.; Bendelac, Albert; Department of Microbiology & Immunology, IU School of Medicine
    Induction of Bcl6 (B cell lymphoma 6) is essential for T follicular helper (Tfh) cell differentiation of antigen-stimulated CD4(+) T cells. Intriguingly, we found that Bcl6 was also highly and transiently expressed during the CD4(+)CD8(+) (double positive [DP]) stage of T cell development, in association with the E3 ligase cullin 3 (Cul3), a novel binding partner of Bcl6 which ubiquitinates histone proteins. DP stage-specific deletion of the E3 ligase Cul3, or of Bcl6, induced the derepression of the Bcl6 target genes Batf (basic leucine zipper transcription factor, ATF-like) and Bcl6, in part through epigenetic modifications of CD4(+) single-positive thymocytes. Although they maintained an apparently normal phenotype after emigration, they expressed increased amounts of Batf and Bcl6 at basal state and produced explosive and prolonged Tfh responses upon subsequent antigen encounter. Ablation of Cul3 in mature CD4(+) splenocytes also resulted in dramatically exaggerated Tfh responses. Thus, although previous studies have emphasized the essential role of Bcl6 in inducing Tfh responses, our findings reveal that Bcl6-Cul3 complexes also provide essential negative feedback regulation during both thymocyte development and T cell activation to restrain excessive Tfh responses.