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Although poorly understood, the signals delivered through this crosstalk substantially alter dendritic cell biology. This is well illustrated with release of TNF-\u03b1\/IL-1\u03b2 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\u20136 Gy) markedly suppressed IL-23 secretion by activated dendritic cells (P &amp;lt; 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-1\u03b2, -6, -10, and -27 or TNF-\u03b1 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-\u03b1\/IL-1\u03b2 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.<\/jats:p>","DOI":"10.1189\/jlb.3a1015-474r","type":"journal-article","created":{"date-parts":[[2016,4,6]],"date-time":"2016-04-06T03:48:33Z","timestamp":1459914513000},"page":"381-389","source":"Crossref","is-referenced-by-count":21,"title":["Stromal fibroblasts support dendritic cells to maintain IL-23\/Th17 responses after exposure to ionizing radiation"],"prefix":"10.1093","volume":"100","author":[{"given":"Anna","family":"Malecka","sequence":"first","affiliation":[{"name":"Host-Tumour Interactions Group, University of Nottingham , Nottingham , United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qunwei","family":"Wang","sequence":"additional","affiliation":[{"name":"Host-Tumour Interactions Group, University of Nottingham , Nottingham , United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabaria","family":"Shah","sequence":"additional","affiliation":[{"name":"Host-Tumour Interactions Group, University of Nottingham , Nottingham , United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruhcha V","family":"Sutavani","sequence":"additional","affiliation":[{"name":"Cancer Immunotherapy Group, Division of Cancer and Stem Cells, University of Nottingham , Nottingham , United Kingdom"},{"name":"Cell Signalling and Immunology, University of Dundee , Scotland , United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian","family":"Spendlove","sequence":"additional","affiliation":[{"name":"Cancer Immunotherapy Group, Division of Cancer and Stem Cells, University of Nottingham , Nottingham , United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judith M","family":"Ramage","sequence":"additional","affiliation":[{"name":"Cancer Immunotherapy Group, Division of Cancer and Stem Cells, University of Nottingham , Nottingham , United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Greensmith","sequence":"additional","affiliation":[{"name":"Host-Tumour Interactions Group, University of Nottingham , Nottingham , United Kingdom"},{"name":"Intelligent Modelling and Analysis Research Group, University of Nottingham , Nottingham , United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hester A","family":"Franks","sequence":"additional","affiliation":[{"name":"Host-Tumour Interactions Group, University of Nottingham , Nottingham , United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J","family":"Gough","sequence":"additional","affiliation":[{"name":"Earle A. 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