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

• Published in: European journal of immunology 2021-01, Vol.51 (1), p.76-90
• Main Authors: Aparicio‐Domingo, Patricia, Cannelle, Hélène, Buechler, Matthew B., Nguyen, Sylvain, Kallert, Sandra M., Favre, Stéphanie, Alouche, Nagham, Papazian, Natalie, Ludewig, Burkhard, Cupedo, Tom, Pinschewer, Daniel D., Turley, Shannon J., Luther, Sanjiv A.
• Format: Article
• Language: English
• Subjects: Acute Disease; Adaptive Immunity; alarmin; Animals; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; Cell differentiation; Chromatin; Chronic Disease; Chronic infection; Cytokines; Endothelial cells; Endothelial Cells - immunology; fibroblastic reticular cells; Fibroblasts - immunology; FRC; Homeostasis; Humans; Immunity, Innate; Infections; Interleukin-33 - deficiency; Interleukin-33 - genetics; Interleukin-33 - metabolism; Interleukin‐33; LCMV; Lymph nodes; Lymph Nodes - immunology; Lymphocytes; Lymphocytes T; Lymphocytic Choriomeningitis - immunology; Lymphocytic choriomeningitis virus - immunology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Models, Immunological; Transcription; Viral infections
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.201948413

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.