Promoter-dependent IRF8 induction governs subset-specific cDC2 reprogramming during infection with intracellular pathogens — ASN Events
  1. Schedule
  2. Plenary 1: DC Development, Lineage Specification & Transcriptional Control
  3. Promoter-dependent IRF8 induction governs subset-specific cDC2 reprogramming during infection with intracellular pathogens

Promoter-dependent IRF8 induction governs subset-specific cDC2 reprogramming during infection with intracellular pathogens (140091)

Kenta Kikuchi 1 , Kandai Ito 1 , Anastasiia Shuliak 1 , Wataru Kawase 2 , Yusuke Tsujimura 3 , Shota Torigoe 3 , Kei-ichiro Yasunaga 4 , Fuki Kudoh 5 , Keita Saeki 5 , Tiyun Wu 5 , Koutarou Nishimura 2 , Terumasa Umemoto 6 , Yutaka Suzuki 7 , Takayuki Yoshimoto 8 , Manabu Ato 3 , Akira Nishiyama 2 , Kisaburo Nagamune 9 , Pedro P. Rocha 10 , Kimi Araki 11 , Keiko Ozato 5 , Tomohiko Tamura 2 , Daisuke Kurotaki 1 12
  1. Laboratory of Chromatin Organization in Immune Cell Development, IRCMS, Kumamoto University, Kumamoto, Japan
  2. Department of Immunology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
  3. Leprosy Research Center, National Institute of Infectious Diseases, Japan Institute for Health Security, Tokyo, Japan
  4. Liaison Laboratory Research Promotion Center, IMEG, Kumamoto University, Kumamoto, Japan
  5. Program in Genomics of Differentiation, NICHD, NIH, Bethesda, MD, Japan
  6. Laboratory of Hematopoietic Stem Cell Engineering, IRCMS, Kumamoto University, Kumamoto, Japan
  7. Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan
  8. Department of Immunoregulation, Institute of Medical Science, Tokyo Medical University, Tokyo, Japan
  9. Department of Parasitology, National Institute of Infectious Diseases, Tokyo, Japan
  10. Unit on Genome Structure and Regulation, NICHD, NIH, Bethesda, MD, Japan
  11. Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, Japan
  12. Laboratory of Chromatin Structure in Immunity, Institute of Photonics and Human Health Frontier, Tokushima University, Tokushima, Japan

Classical dendritic cells (cDCs) comprise cDC1s and heterogeneous cDC2s, including ESAM+ cDC2As and ESAM− cDC2Bs. While cDC2s exhibit substantial phenotypic and functional diversity under inflammatory conditions, the mechanisms by which environmental cues reprogram cDC2 identity remain incompletely understood. Here, we identify a distinct inflammatory cDC2 subset expressing XCR1 (XCR1+ inf-cDC2) that emerges during infection with intracellular pathogens such as Toxoplasma gondii and Mycobacterium tuberculosis. Through the IL-12–IFN-γ cytokine axis, ESAM− cDC2Bs preferentially undergo a state transition into XCR1+ inf-cDC2s, acquiring hybrid features of both cDC1s and cDC2Bs. Integrative epigenomic analyses revealed that cis-regulatory regions associated with XCR1+ inf-cDC2-specific genes are epigenetically pre-primed in ESAM− cDC2Bs prior to inflammatory stimulation, characterized by increased chromatin accessibility without full activation. Upon stimulation, these genomic regions gain activation marks, enabling rapid transcriptional induction. Mechanistically, we show that STAT1 binding to the Irf8 promoter, rather than the canonical cDC1-specific +32 kb enhancer, is essential for inducing Irf8 expression and driving the differentiation of XCR1+ inf-cDC2s. Genetic disruption of this promoter-dependent regulatory mechanism selectively impairs the generation of XCR1+ inf-cDC2s without affecting steady-state DC development, resulting in compromised host defense against intracellular pathogens. Collectively, our findings reveal that inflammatory environments exploit subset-specific epigenetic priming to direct cDC2 state transitions via distinct cis-regulatory programs. This work provides a mechanistic framework linking developmental origin, chromatin state, and functional plasticity in DC responses, and highlights a previously unrecognized pathway by which cDC2 subsets contribute to type 1 immunity.