Fibroblast-derived IL-33 is dispensable for lymph node homeostasis but critical for CD8 T-cell responses to acute and chronic viral infection

P Aparicio-Domingo, H Cannelle, MB Buechler, S Nguyen, SM Kallert, S Favre, N Alouche, Natalie Papazian, B Ludewig, Tom Cupedo, DD Pinschewer, SJ Turley, SA Luther

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Abstract

Upon viral infection, stressed or damaged cells can release alarmins like IL-33 that act as endogenous danger signals alerting innate and adaptive immune cells. IL-33 coming from nonhematopoietic cells has been identified as important factor triggering the expansion of antiviral CD8+ T cells. In LN the critical cellular source of IL-33 is unknown, as is its potential cell-intrinsic function as a chromatin-associated factor. Using IL-33-GFP reporter mice, we identify fibroblastic reticular cells (FRC) and lymphatic endothelial cells (LEC) as the main IL-33 source. In homeostasis, IL-33 is dispensable as a transcriptional regulator in FRC, indicating it functions mainly as released cytokine. Early during infection with lymphocytic choriomeningitis virus (LCMV) clone 13, both FRC and LEC lose IL-33 protein expression suggesting cytokine release, correlating timewise with IL-33 receptor expression by reactive CD8+ T cells and their greatly augmented expansion in WT versus ll33−/− mice. Using mice lacking IL-33 selectively in FRC versus LEC, we identify FRC as key IL-33 source driving acute and chronic antiviral T-cell responses. Collectively, these findings show that LN T-zone FRC not only regulate the homeostasis of naïve T cells but also their expansion and differentiation several days into an antiviral response.

Original languageEnglish
Pages (from-to)76-90
Number of pages15
JournalEuropean Journal of Immunology
Volume51
Issue number1
Early online date22 Jul 2020
DOIs
Publication statusPublished - Jan 2021

Bibliographical note

Funding Information:
We thank Karin Schaeuble, Leonardo Scarpellino, Leonor Morgado, Katambayi Muamba Kamanda, Wilson Castro, Loriane Savary (University of Lausanne), and Min Lu (University of Basel) for technical help. Hirohisa Saito (National Research Institute for Child Health & Development, Tokyo, Japan) and Yasuhide Furuta (LARGE, RIKEN BDR‐ RIKEN Center for Biosystems Dynamics Research, Kobe, Japan) for allowing to use their mice and R.T. Lee (Harvard University, Boston, USA) for mice, Taija Mäkinen (Uppsala University, Sweden) and Tatiana Petrova (University of Lausanne) for sharing Prox1‐creERT2 mice, Doron Merkler (University of Geneva, Geneva, Switzerland) and Max Löhning (Charité, Universitätsmedizin Berlin, Germany) for critical discussions and sharing tools; Stokes Peebles for critical reading of the manuscript. This project has received funding from the European Union's Horizon 2020 research and innovation program under the Marie Skłodowska‐Curie grant agreement (No 708715 to PAD) and by the Swiss National Science Foundation (SNF) Sinergia program (CRSII3_160772 to D.D.P. and S.A.L.) and an individual SNF grant (166500 to B.L.). We thank the mouse, microscopy and flow cytometry facility at the University of Lausanne; the Genentech animal core groups for animal care and genotyping analysis, and the Genentech core facility staff for bioinformatics assistance. Il33 −/− Il33 flox/flox

Funding Information:
We thank Karin Schaeuble, Leonardo Scarpellino, Leonor Morgado, Katambayi Muamba Kamanda, Wilson Castro, Loriane Savary (University of Lausanne), and Min Lu (University of Basel) for technical help. Hirohisa Saito (National Research Institute for Child Health & Development, Tokyo, Japan) and Yasuhide Furuta (LARGE, RIKEN BDR- RIKEN Center for Biosystems Dynamics Research, Kobe, Japan) for allowing to use their Il33−/− mice and R.T. Lee (Harvard University, Boston, USA) for Il33flox/flox mice, Taija Mäkinen (Uppsala University, Sweden) and Tatiana Petrova (University of Lausanne) for sharing Prox1-creERT2 mice, Doron Merkler (University of Geneva, Geneva, Switzerland) and Max Löhning (Charité, Universitätsmedizin Berlin, Germany) for critical discussions and sharing tools; Stokes Peebles for critical reading of the manuscript. This project has received funding from the European Union's Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement (No 708715 to PAD) and by the Swiss National Science Foundation (SNF) Sinergia program (CRSII3_160772 to D.D.P. and S.A.L.) and an individual SNF grant (166500 to B.L.). We thank the mouse, microscopy and flow cytometry facility at the University of Lausanne; the Genentech animal core groups for animal care and genotyping analysis, and the Genentech core facility staff for bioinformatics assistance.

Publisher Copyright:
© 2020 Wiley-VCH GmbH

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