Characterization of BATF functions in plasmacytoid dendritic cell development and type I interferon production in antiviral immune responses

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Plasmacytoid dendritic cells (pDCs) harbor the capacity to produce high amounts of type I interferons (IFNs). Thereby, pDCs play an important and complex role in viral infections mediating protective immune responses or causing immunopathology. Also, dysregulated activation of pDCs is associated with autoimmune diseases. The cellular and molecular mechanisms of pDC mediated immune regulation are poorly understood. In aiming to identify novel regulators of pDC functions we discovered a high expression of Batf (Basic leucine zipper transcription factor, ATF-like) in IFN beta-producing pDCs. BATF together with BATF2 and BATF3 comprise a subfamily of the larger group of AP-1 transcription factors. It is known to negatively regulate AP-1 mediated gene transcription, but also to exert positive transcriptional activities by interacting with other transcription factors such as IRF family members. BATF has been shown to be essential in the differentiation and cytokine production of T helper (Th) cell types and in class switch recombination in B cells. No implications for BATF in pDC development or function are known so far.In preliminary studies we made the following observations: (i) BATF is highly expressed in type I IFN producing pDCs, (ii) frequencies of pDCs are increased in Flt3-L cultures and after Toll like receptor (TLR) 9 activation in secondary lymphoid organs from Batf-deficient (Batf-/-) mice, (iii) surface expression levels of the DC marker CD11c are reduced on Batf-/- pDCs, (iv) increased amounts of type I IFN are produced by Batf-/- pDCs in response to TLR9 activation in vitro and present in the serum of lymphocytic choriomeningitis virus (LCMV) infected Batf-/- mice, and (v) viral infection rates in vitro in the presence of Batf-/- pDCs are reduced, as compared to Batf+/+ littermate controls, respectively. Also, (vi) a type I IFN signature and differences in the expression of DC differentiation genes are visible in preliminary transcriptome profiling of Batf-/- vs. Batf+/+ pDCs.The proposed study will define the mechanisms of BATF-mediated functions in pDC development and effector functions in anti-viral immunity. Our envisaged twin-track work programme covers molecular and cellular aspects: In the first track we will define the molecular mechanisms of BATF-mediated regulation of type I IFN production in pDCs and perform genome wide profiling of transcriptional and epigenetic temporal patterns in Batf-/- vs. Batf+/+ pDCs after activation and identify BATF-interaction partners within the activating complex. The second track investigates the role of BATF in pDC development and differentiation using pDC specific BATF-deficient mice and competitive bone marrow chimeras and characterizes pDC specific BATF functions in LCMV infection.Detailed analyses of the functions and pathways regulated by BATF in pDCs will provide critical information for controlled manipulation of BATF functions in infectious diseases and interferonopathies.