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

Abstract

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.

The interaction of intestinal microbiota and innate lymphoid cells in health and disease throughout life

“…Here, upon oral MHV infection, fibroblastic reticular cells (FRCs) secrete IL‐15 in a MyD88‐dependent manner and thereby control ILC1s and intestinal inflammation. Dysbiosis is observed in the absence of innate immune stimulation, showing that tissue circuits between non‐haematopoietic cells, such as FRCs and haematopoietic cells including ILC1s, are key in intestinal immune responses against viruses …”

“…Dysbiosis is observed in the absence of innate immune stimulation, showing that tissue circuits between non-haematopoietic cells, such as FRCs and haematopoietic cells including ILC1s, are key in intestinal immune responses against viruses. 121 Although respiratory viruses, including influenza virus (ssRNA), are limited to the airways during infection and have been reported to impact systemic immunity and the intestinal microbiota. 122,123 Indeed, immunity and microbiota of the gut and lungs are closely interlinked.…”

STAT1 Represses Cytokine-Producing Group 2 and Group 3 Innate Lymphoid Cells during Viral Infection

“…Similarly, the activation of CD4 + Th2 and Th17 cells has previously been associated with maladaptive immunopathology and enhanced disease severity in the context of viral infection (10–14). Conversely, ILC1 have been shown to produce anti-viral mediators in the context of viral infection and/or enhance viral clearance (15–17). …”

Anatomical Uniqueness of the Mucosal Immune System (GALT, NALT, iBALT) for the Induction and Regulation of Mucosal Immunity and Tolerance

“…Although FRCs are primarily associated with the T cell zones of lymphoid organs, they also extend into the B cell follicles, where they express IL-7 and BAFF [120], which maintains the viability of B cells. Finally, FRCs in Peyer's patches modulate the activity of ILC1 cells through the transpresentation of IL-15 [121]. Thus FRCs are essential for the placement, movement, and survival of a variety of hematopoietic cell types.…”