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Browsing by Author "Bendelac, Albert"
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Item Innate and adaptive humoral responses coat distinct commensal bacteria with immunoglobulin A(Elsevier, 2015-09-15) Bunker, Jeffrey J.; Flynn, Theodore M.; Koval, Jason C.; Shaw, Dustin G.; Meisel, Marlies; McDonald, Benjamin D.; Ishizuka, Isabel E.; Dent, Alexander L.; Wilson, Patrick C.; Jabri, Bana; Antonopoulos, Dionysios A.; Bendelac, Albert; Department of Microbiology and Immunology, IU School of MedicineImmunoglobulin A (IgA) is prominently secreted at mucosal surfaces and coats a fraction of the intestinal microbiota. However, the commensal bacteria bound by IgA are poorly characterized and the type of humoral immunity they elicit remains elusive. We used bacterial flow cytometry coupled with 16S rRNA gene sequencing (IgA-Seq) in murine models of immunodeficiency to identify IgA-bound bacteria and elucidate mechanisms of commensal IgA targeting. We found that residence in the small intestine, rather than bacterial identity, dictated induction of specific IgA. Most commensals elicited strong T-independent (TI) responses that originated from the orphan B1b lineage and from B2 cells, but excluded natural antibacterial B1a specificities. Atypical commensals including segmented filamentous bacteria and Mucispirillum evaded TI responses but elicited T-dependent IgA. These data demonstrate exquisite targeting of distinct commensal bacteria by multiple layers of humoral immunity and reveal a specialized function of the B1b lineage in TI mucosal IgA responses.Item 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 MedicineInduction 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.