BATF2 promotes HSC myeloid differentiation by amplifying IFN response mediators during chronic infection

Duy T Le; Marcus A Florez; Pawel Kus; Brandon T Tran; Bailee Kain; Yingmin Zhu; Kurt Christensen; Antrix Jain; Anna Malovannaya; Katherine Y King

doi:10.1016/j.isci.2023.106059

BATF2 promotes HSC myeloid differentiation by amplifying IFN response mediators during chronic infection

iScience. 2023 Jan 27;26(2):106059. doi: 10.1016/j.isci.2023.106059. eCollection 2023 Feb 17.

Authors

Duy T Le^{1

2}, Marcus A Florez^{2

3}, Pawel Kus⁴, Brandon T Tran^{2

5}, Bailee Kain^{2

3}, Yingmin Zhu⁶, Kurt Christensen⁶, Antrix Jain⁷, Anna Malovannaya^{7

8}, Katherine Y King^{1

2}

Affiliations

¹ Graduate Program in Immunology, Graduate School of Biomedical Sciences (GSBS), Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, USA.
² Department of Pediatrics, Division of Infectious Diseases, Baylor College of Medicine, 1102 Bates Street Suite 1150, Houston, TX, USA.
³ Graduate Program in Translational Biology and Molecular Medicine, GSBS, Baylor College of Medicine, Houston, TX, USA.
⁴ Department of Systems Biology and Engineering, Silesian University of Technology, Gliwice, Poland.
⁵ Graduate Program in Cancer and Cell Biology, GSBS, Baylor College of Medicine, Houston, TX, USA.
⁶ Protein and Antibody Production Core, Baylor College of Medicine, Houston, TX, USA.
⁷ Mass Spectrometry Proteomics Core, Baylor College of Medicine, Houston, TX, USA.
⁸ Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, USA.

Abstract

Basic leucine zipper ATF-like transcription factor 2 (BATF2), an interferon-activated immune response regulator, is a key factor responsible for myeloid differentiation and depletion of HSC during chronic infection. To delineate the mechanism of BATF2 function in HSCs, we assessed Batf2 KO mice during chronic infection and found that they produced less pro-inflammatory cytokines, less immune cell recruitment to the spleen, and impaired myeloid differentiation with better preservation of HSC capacity compared to WT. Co-IP analysis revealed that BATF2 forms a complex with JUN to amplify pro-inflammatory signaling pathways including CCL5 during infection. Blockade of CCL5 receptors phenocopied Batf2 KO differentiation defects, whereas treatment with recombinant CCL5 was sufficient to rescue IFNγ-induced myeloid differentiation and recruit more immune cells to the spleen in Batf2 KO mice. By revealing the mechanism of BATF2-induced myeloid differentiation of HSCs, these studies elucidate potential therapeutic strategies to boost immunity while preserving HSC function during chronic infection.

Keywords: Biological sciences; Immunology; Molecular physiology.

Abstract

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