BATF2 a Controversial Modulator of Innate Immune Signaling

Maximilian Appel1, Maximilian Nastaly1, Gabor Zsurka2, Tobias Baumgartner2, Wolfram Kunz2, Gunther Hartmann1, Eva Bartok1

1 Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany
2 Department of Experimental Epileptology and Cognition Research, Life&Brain Center, University of Bonn, Bonn, Germany

Basic Leucine Zipper ATF-Like Transcription Factor 2 (BATF2) is a relatively newly discovered gene with controversial function. Initially, using overexpression in human cells, BATF2 was reported to sequester c-Jun and inhibit AP-1 signaling, but subsequent studies in BATF2-/- mice instead demonstrated a decrease in the release of the AP-1 downstream cytokines IL-12p40 and TNF upon immune stimulation. Since no genetic proof of the role of human BATF2 has been provided to date, we generated BATF2-/- THP-1 cells, a human monocytic cell line. Here, we observed a reduction in the cytokine response to TLR2 and TLR4 in line with the BATF2-/- mouse but also a strongly enhanced response to TLR8 stimulation, a TLR which is not active in mice. Moreover, immune stimulation of the peripheral blood monocytic cells (PBMC) of 3 siblings homozygous for a Q19* nonsense mutation in BATF2, who have profound neurodevelopmental defects, also demonstrated enhanced TLR8 activity. Quite unexpectedly, 3’ mRNA sequencing revealed that both patient PBMC and BATF2 -/- THP-1 cells had a constitutive interferon-stimulated gene (ISG) signature, consistent with a type-I interferonopathy, a group of diseases also known to have a profound neurological phenotype in humans. Currently, we are characterizing the immune pathway responsible for ISG upregulation in these cells and the precise role of AP-1 signaling for TLR8 versus TLR2 and TLR4 in human cells. We aim to decipher the precise role of BATF2-/- as a modulator of human immune signaling in order to better understand how BATF2 hypomorphy contributes to neurological disease in human patients.