Dermal IRF4+ dendritic cells and monocytes license CD4+ T helper cells to distinct cytokine profiles

Nat Commun. 2020 Nov 6;11(1):5637. doi: 10.1038/s41467-020-19463-9. | PubMed

Kerry L Hilligan^1,2,3, Shiau-Choot Tang¹, Evelyn J Hyde¹, Elsa Roussel¹, Johannes U Mayer¹, Jianping Yang¹, Kirsty A Wakelin¹, Alfonso J Schmidt¹, Lisa M Connor^1,4, Alan Sher³, Andrew S MacDonald⁵, Franca Ronchese⁶

1. Malaghan Institute of Medical Research, Wellington, 6012, New Zealand.
2. Department of Pathology and Molecular Medicine, University of Otago Wellington, Wellington, 6021, New Zealand.
3. Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, 20892, MD, USA.
4. School of Biological Sciences, Victoria University of Wellington, Wellington, 6012, New Zealand.
5. Lydia Becker Institute of Immunology and Inflammation, Manchester Collaborative Centre for Inflammation Research, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
6. Malaghan Institute of Medical Research, Wellington, 6012, New Zealand. fronchese@malaghan.org.nz.

Abstract

Antigen (Ag)-presenting cells (APC) instruct CD4+ helper T (Th) cell responses, but it is unclear whether different APC subsets contribute uniquely in determining Th differentiation in pathogen-specific settings. Here, we use skin-relevant, fluorescently-labeled bacterial, helminth or fungal pathogens to track and characterize the APC populations that drive Th responses in vivo. All pathogens are taken up by a population of IRF4+ dermal migratory dendritic cells (migDC2) that similarly upregulate surface co-stimulatory molecules but express pathogen-specific cytokine and chemokine transcripts. Depletion of migDC2 reduces the amount of Ag in lymph node and the development of IFNγ, IL-4 and IL-17A responses without gain of other cytokine responses. Ag+ monocytes are an essential source of IL-12 for both innate and adaptive IFNγ production, and inhibit follicular Th cell development. Our results thus suggest that Th cell differentiation does not require specialized APC subsets, but is driven by inducible and pathogen-specific transcriptional programs in Ag+ migDC2 and monocytes.

Presented By Kerry Hilligan