Absence of Batf3 reveals a new dimension of cell state heterogeneity within conventional dendritic cells

Samuel W Lukowski; Inga Rødahl; Samuel Kelly; Meihua Yu; James Gotley; Chenhao Zhou; Susan Millard; Stacey B Andersen; Angelika N Christ; Gabrielle Belz; Ian H Frazer; Janin Chandra

doi:10.1016/j.isci.2021.102402

Absence of Batf3 reveals a new dimension of cell state heterogeneity within conventional dendritic cells

iScience. 2021 Apr 15;24(5):102402. doi: 10.1016/j.isci.2021.102402. eCollection 2021 May 21.

Authors

Samuel W Lukowski^{1

2}, Inga Rødahl², Samuel Kelly², Meihua Yu², James Gotley², Chenhao Zhou², Susan Millard³, Stacey B Andersen¹, Angelika N Christ¹, Gabrielle Belz^{2

4

5}, Ian H Frazer², Janin Chandra²

Affiliations

¹ The Institute for Molecular Bioscience, The University of Queensland, 4067, QLD, Australia.
² The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, QLD 4102, Australia.
³ Mater Research, Translational Research Institute, Woolloongabba, 4102 QLD, Australia.
⁴ The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.
⁵ Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia.

Abstract

Conventional dendritic cells (cDCs) are traditionally subdivided into cDC1 and cDC2 lineages. Batf3 is a cDC1-required transcription factor, and we observed that Batf3-/- mice harbor a population of cDC1-like cells co-expressing cDC2-associated surface molecules. Using single-cell RNA sequencing with integrated cell surface protein expression (CITE-seq), we found that Batf3-/- mitotic immature cDC1-like cells showed reduced expression of cDC1 features and increased levels of cDC2 features. In wild type, we also observed a proportion of mature cDC1 cells expressing surface features characteristic to cDC2 and found that overall cDC cell state heterogeneity was mainly driven by developmental stage, proliferation, and maturity. We detected population diversity within Sirpa+ cDC2 cells, including a Cd33+ cell state expressing high levels of Sox4 and lineage-mixed features characteristic to cDC1, cDC2, pDCs, and monocytes. In conclusion, these data suggest that multiple cDC cell states can co-express lineage-overlapping features, revealing a level of previously unappreciated cDC plasticity.

Keywords: Cell Biology; Immunology; Transcriptomics.