4 th International Conference and Exhibition on Immunology Batf is essential for IL-4 expression in T follicular helper cells. Roza Nurieva Center for.

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Presentation transcript:

4 th International Conference and Exhibition on Immunology Batf is essential for IL-4 expression in T follicular helper cells. Roza Nurieva Center for Cancer Immunology Research, MD Anderson Cancer Center. Houston, TX. USA

T helper subsets: differentiation and function BMC Biology, th International Conference and Exhibition on Immunology

Tfh TH2 Tfh IL-4 Transcriptional control of T helper subsets Roza Nurieva 4 th International Conference and Exhibition on Immunology

GATA3  In Tfh cells: CNS2 element of the IL-4 locus and TFs?  In Th2 cells: Various Cis-Regulatory Elements including Il4 Promoter and TFS Il-4 transcription in Th2 and Tfh cells The 3′ enhancer CNS2 is a critical regulator of interleukin-4-mediated humoral immunity in follicular helper T cells. Immunity, Blood, th International Conference and Exhibition on Immunology

 Batf belongs to the AP-1/ATF superfamily of transcription factors and is thought to be a negative regulator of AP-1/ATF transcriptional events.  The AP-1 transcription factor Batf controls TH17 differentiation. Nature,2009  Batf coordinates multiple aspects of B and T cell function required for normal antibody responses. Journal of experimental medicine,2010. Nature immunology, Basic leucine zipper transcription factor, ATF-like(BATF) Nature Immunology, th International Conference and Exhibition on Immunology

Batf is expressed in Th2 and Tfh cells A. B.  CD4+CD44hiCXCR5hiPD1hi (Tfh)  CD4+CD44hiCXCR5- (nTfh)  Active histone modifications (AcH3,H3k4) 4 th International Conference and Exhibition on Immunology

Batf deficiency abrogates Th2 cytokines in vivo  WT and Batf deficient mice immunized with ovalbumin in alum. 4 th International Conference and Exhibition on Immunology

Batf has partial control over Th2 genes in vitro C. * B. A. 4 th International Conference and Exhibition on Immunology

The IL-4 defect in Tfh cells upon Batf deficiency is T cell intrinsic 4 th International Conference and Exhibition on Immunology

Asthma Sort Tfh cells iv transfer Intra nasal ova for 3 days Analysis WT and Batf KO mice (CD45.2+) C. B. A. IL-4 producing Tfh cells can trigger asthmatic symptoms B6SJL mice (CD45.1+) 2X10^5 cells 4 th International Conference and Exhibition on Immunology

GATA3  In Tfh cells: CNS2 element of the IL-4 locus and TFs?  In Th2 cells: Cis-Regulatory Elements including Il4 Promoter Il-4 transcription in Th2 and Tfh cells The 3′ enhancer CNS2 is a critical regulator of interleukin-4-mediated humoral immunity in follicular helper T cells. Immunity, Blood, th International Conference and Exhibition on Immunology

Batf in cooperation with IRF4 regulates IL-4 expression in Tfh cells through the CNS2 locus 4 th International Conference and Exhibition on Immunology

Batf/IRF4 along with Stat3 and Stat6 controls IL-4 production in Tfh cells 4 th International Conference and Exhibition on Immunology

Summary  The transcription factor Batf, a member of the AP-1/Jun family, shows enhanced expression in both Th2 and Tfh cells.  Functionally, Batf is required for IL-4 expression in Tfh cells and its deficiency leads to subsequent reduction in their pro-allergic function.  Batf in cooperation with IRF4 and along with Stat3 and Stat6 controls IL-4 production in Tfh cells by directly binding to and activation of the CNS2 region of the IL-4 locus. These results indicate a critical role of Batf in promoting the generation of pro-allergic IL-4 producing Tfh cells. 4 th International Conference and Exhibition on Immunology

Acknowledgement Roza Nurieva Anupama Sahoo Andrei Alekseev Lydia Obertas Beatrisa Lerman Divyendu Singh Shradha Wali Sushant Puri Dr. Chen Dong Kentaro Tanaka MD Anderson FACS Core facility 4 th International Conference and Exhibition on Immunology