Transcriptional programming mediated by the histone demethylase KDM5C regulates dendritic cell population heterogeneity and function
Hannah Guak,
Matthew Weiland,
Alexandra Vander Ark,
Lukai Zhai,
Kin Lau,
Mario Corrado,
Paula Davidson,
Ebenezer Asiedu,
Batsirai Mabvakure,
Shelby Compton,
Lisa DeCamp,
Catherine A. Scullion,
Russell G. Jones,
Sara M. Nowinski,
Connie M. Krawczyk
Affiliations
Hannah Guak
Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI 49503, USA; Department of Pediatrics, University of Michigan, Ann Arbor, MI 48109, USA
Matthew Weiland
Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI 49503, USA
Alexandra Vander Ark
Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI 49503, USA
Lukai Zhai
Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI 49503, USA
Kin Lau
Bioinformatics and Biostatistics Core, Van Andel Institute, Grand Rapids, MI 49503, USA
Mario Corrado
Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI 49503, USA; Department of Internal Medicine, University of Toronto, Toronto, ON M5S 3H2, Canada
Paula Davidson
Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI 49503, USA
Ebenezer Asiedu
Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI 49503, USA
Batsirai Mabvakure
Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI 49503, USA; Department of Oncology, Georgetown University School of Medicine, Washington, DC 20057, USA; Georgetown Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA
Shelby Compton
Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI 49503, USA
Lisa DeCamp
Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI 49503, USA
Catherine A. Scullion
Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI 49503, USA; Department of Experimental Medicine, Dana-Farber Cancer Institute, Boston, MA 02215, USA
Russell G. Jones
Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI 49503, USA
Sara M. Nowinski
Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI 49503, USA
Connie M. Krawczyk
Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI 49503, USA; Corresponding author
Summary: Functional and phenotypic heterogeneity of dendritic cells (DCs) play crucial roles in facilitating the development of diverse immune responses essential for host protection. Here, we report that KDM5C, a histone lysine demethylase, regulates conventional or classical DC (cDC) and plasmacytoid DC (pDC) population heterogeneity and function. Mice deficient in KDM5C in DCs have increased proportions of cDC2Bs and cDC1s, which is partly dependent on type I interferon (IFN) and pDCs. Loss of KDM5C results in an increase in Ly6C− pDCs, which, compared to Ly6C+ pDCs, have limited ability to produce type I IFN and more efficiently stimulate antigen-specific CD8 T cells. KDM5C-deficient DCs have increased expression of inflammatory genes, altered expression of lineage-specific genes, and decreased function. In response to Listeria infection, KDM5C-deficient mice mount reduced CD8 T cell responses due to decreased antigen presentation by cDC1s. Thus, KDM5C is a key regulator of DC heterogeneity and critical driver of the functional properties of DCs.
