title: Stromal fibroblasts support dendritic cells to maintain IL-23/Th17 responses after exposure to ionizing radiation.
abstract: Dendritic cell function is modulated by stromal cells, including fibroblasts. Although poorly understood, the signals delivered through this crosstalk substantially alter dendritic cell biology. This is well illustrated with release of TNF-α/IL-1β from activated dendritic cells, promoting PGE2 secretion from stromal fibroblasts. This instructs dendritic cells to up-regulate IL-23, a key Th17-polarizing cytokine. We previously showed that ionizing radiation inhibited IL-23 production by human dendritic cells in vitro. In the present study, we investigated the hypothesis that dendritic cell-fibroblast crosstalk overcomes the suppressive effect of ionizing radiation to support appropriately polarized Th17 responses. Radiation (1-6 Gy) markedly suppressed IL-23 secretion by activated dendritic cells (P < 0.0001) without adversely impacting their viability and consequently, inhibited the generation of Th17 responses. Cytokine suppression by ionizing radiation was selective, as there was no effect on IL-1β, -6, -10, and -27 or TNF-α and only a modest (11%) decrease in IL-12p70 secretion. Coculture with fibroblasts augmented IL-23 secretion by irradiated dendritic cells and increased Th17 responses. Importantly, in contrast to dendritic cells, irradiated fibroblasts maintained their capacity to respond to TNF-α/IL-1β and produce PGE2, thus providing the key intermediary signals for successful dendritic cell-fibroblasts crosstalk. In summary, stromal fibroblasts support Th17-polarizing cytokine production by dendritic cells that would otherwise be suppressed in an irradiated microenvironment. This has potential ramifications for understanding the immune response to local radiotherapy. These findings underscore the need to account for the impact of microenvironmental factors, including stromal cells, in understanding the control of immunity.
authors.affiliation: Host-Tumour Interactions Group, University of Nottingham, Nottingham, United Kingdom;
authors.forename: Anna
authors.initials: A
authors.lastname: Malecka
authors.affiliation: Host-Tumour Interactions Group, University of Nottingham, Nottingham, United Kingdom;
authors.forename: Qunwei
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Host-Tumour Interactions Group, University of Nottingham, Nottingham, United Kingdom;
authors.forename: Sabaria
authors.initials: S
authors.lastname: Shah
authors.affiliation: Cancer Immunotherapy Group, Division of Cancer and Stem Cells, University of Nottingham, Nottingham, United Kingdom; Cell Signalling and Immunology, University of Dundee, Scotland, United Kingdom;
authors.forename: Ruhcha V
authors.initials: RV
authors.lastname: Sutavani
authors.affiliation: Cancer Immunotherapy Group, Division of Cancer and Stem Cells, University of Nottingham, Nottingham, United Kingdom;
authors.forename: Ian
authors.initials: I
authors.lastname: Spendlove
authors.affiliation: Cancer Immunotherapy Group, Division of Cancer and Stem Cells, University of Nottingham, Nottingham, United Kingdom;
authors.forename: Judith M
authors.initials: JM
authors.lastname: Ramage
authors.affiliation: Host-Tumour Interactions Group, University of Nottingham, Nottingham, United Kingdom; Intelligent Modelling and Analysis Research Group, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Julie
authors.initials: J
authors.lastname: Greensmith
authors.affiliation: Host-Tumour Interactions Group, University of Nottingham, Nottingham, United Kingdom;
authors.forename: Hester A
authors.initials: HA
authors.lastname: Franks
authors.affiliation: Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, Portland, Oregon, USA;
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Gough
authors.affiliation: Klinik fur Dermatologie, University of Leipzig, Germany; and.
authors.forename: Anja
authors.initials: A
authors.lastname: Saalbach
authors.affiliation: Host-Tumour Interactions Group, University of Nottingham, Nottingham, United Kingdom;
authors.forename: Poulam M
authors.initials: PM
authors.lastname: Patel
authors.affiliation: Host-Tumour Interactions Group, University of Nottingham, Nottingham, United Kingdom; andrew.jackson@nottingham.ac.uk.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Jackson
mesh_terms: D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000528:radiation effects; D005347:Fibroblasts / Q000276:immunology* / Q000378:metabolism / Q000528:radiation effects; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D053759:Interleukin-23 / Q000378:metabolism*; D011839:Radiation, Ionizing; D017154:Stromal Cells / Q000276:immunology* / Q000378:metabolism / Q000528:radiation effects; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism / Q000528:radiation effects; D058504:Th17 Cells
chemical_list: D020381:Interleukin-17; D053583:Interleukin-1beta; D053759:Interleukin-23
keywords: cancer; cytokine; immunity