Fibroblastic reticular cells regulate intestinal inflammation via IL-15-mediated control of group 1 ILCs

• Published in: Nature immunology Vol. 17; no. 12; pp. 1388 - 1396
• Main Authors: Gil-Cruz, Cristina, Perez-Shibayama, Christian, Onder, Lucas, Chai, Qian, Cupovic, Jovana, Cheng, Hung-Wei, Novkovic, Mario, Lang, Philipp A, Geuking, Markus B, McCoy, Kathy D, Abe, Shinya, Cui, Guangwei, Ikuta, Koichi, Scandella, Elke, Ludewig, Burkhard
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.12.2016; Nature Publishing Group
• Subjects: 631/250/1620/1616; 631/250/2504/2506; 631/250/347; Animals; B cells; Biomedicine; Cells, Cultured; Citrobacter rodentium - immunology; Coronavirus Infections - immunology; Cytokines; Diseases; Enterobacteriaceae Infections - immunology; Fibroblasts - immunology; Health aspects; Immunity, Innate; Immunology; Infection; Infectious Diseases; Inflammation; Interleukin-15 - metabolism; Lymph nodes; Lymph Nodes - pathology; Lymphocytes; Lymphocytes - immunology; Medical schools; Mice; Mice, Inbred C57BL; Mice, Knockout; Murine hepatitis virus - immunology; Myeloid Differentiation Factor 88 - genetics; Myeloid Differentiation Factor 88 - metabolism; Peyer's Patches - pathology; T cells; Th1 Cells - immunology; Toll-Like Receptor 7 - genetics; Toll-Like Receptor 7 - metabolism
• ISSN: 1529-2908; 1529-2916
• DOI: 10.1038/ni.3566

Fibroblastic reticular cells influence the function of lymphocytes in secondary lymphoid organs. Ludewig and colleagues demonstrate that they also specifically restrain the activation of group 1 innate lymphoid cells in the presence of microbial stimulation to prevent immunopathology. Fibroblastic reticular cells (FRCs) of secondary lymphoid organs form distinct niches for interaction with hematopoietic cells. We found here that production of the cytokine IL-15 by FRCs was essential for the maintenance of group 1 innate lymphoid cells (ILCs) in Peyer's patches and mesenteric lymph nodes. Moreover, FRC-specific ablation of the innate immunological sensing adaptor MyD88 unleashed IL-15 production by FRCs during infection with an enteropathogenic virus, which led to hyperactivation of group 1 ILCs and substantially altered the differentiation of helper T cells. Accelerated clearance of virus by group 1 ILCs precipitated severe intestinal inflammatory disease with commensal dysbiosis, loss of intestinal barrier function and diminished resistance to colonization. In sum, FRCs act as an 'on-demand' immunological 'rheostat' by restraining activation of group 1 ILCs and thereby preventing immunopathological damage in the intestine.