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.

Additional Metadata
Keywords alarmin, fibroblastic reticular cells, FRC, Interleukin-33, LCMV
Persistent URL dx.doi.org/10.1002/eji.201948413, hdl.handle.net/1765/129390
Journal European Journal of Immunology
Organisation Department of Hematology
Citation
Aparicio-Domingo, P, Cannelle, H. (Hélène), Buechler, M.B. (Matthew B.), Nguyen, S. (Sylvain), Kallert, S.M. (Sandra M.), Favre, S. (Stéphanie), … Luther, S.A. (Sanjiv A.). (2020). Fibroblast-derived IL-33 is dispensable for lymph node homeostasis but critical for CD8 T-cell responses to acute and chronic viral infection. European Journal of Immunology. doi:10.1002/eji.201948413