Type I interferon signaling in fibroblastic reticular cells prevents exhaustive activation of antiviral CD8 ⁺ T cells

Abstract

Fibroblastic reticular cells (FRCs) are stromal cells that actively promote the induction of immune responses by coordinating the interaction of innate and adaptive immune cells. However, whether and to which extent immune cell activation is determined by lymph node FRC reprogramming during acute viral infection has remained unexplored. Here, we genetically ablated expression of the type I interferon-α receptor (Ifnar) in Ccl19-Cre+ cells and found that sensing of type I interferon imprints an antiviral state in FRCs and thereby preserves myeloid cell composition in lymph nodes of naive mice. During localized lymphocytic choriomeningitis virus infection, IFNAR signaling precipitated profound phenotypic adaptation of all FRC subsets enhancing antigen presentation, chemokine-driven immune cell recruitment, and immune regulation. The IFNAR-dependent shift of all FRC subsets toward an immunostimulatory state reduced exhaustive CD8+ T cell activation. In sum, these results unveil intricate circuits underlying type I IFN sensing in lymph node FRCs that enable protective antiviral immunity.

Fibroblastic reticular cell lineage convergence in Peyer’s patches governs intestinal immunity

“…1d and Extended Data Fig. 2g), indicating a switch of TRC3 to an activated state 27 . High-resolution confocal microscopy of Ccl19 EYFP PPs confirmed the presence of ACTA2 lo LUM hi TRC2/3 in the center of the T cell zone (Fig.…”

“…FRC lineage convergence supports anticoronavirus B cell responses. FRCs of lymph nodes have been recognized as key players for the generation of protective immunity against viral infections 10,11,27 . PP FRCs of the Ccl19 Cre lineage regulate intestinal inflammation during infection with the murine coronavirus (M-CoV) via IL-15-mediated control of group 1 ILCs 7 .…”

Cross-tissue organization of the fibroblast lineage

“…The steady-state fibroblast atlas was composed of 28 datasets 10,18-21,31, [53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70] and the perturbed-state fibroblast atlas was composed of 17 datasets 10,18,21,31, [53][54][55][56][57][58]61,[69][70][71] . Integrated fibroblast atlases at steady and perturbed states were generated and analysed using the following steps:…”

LN-Derived Fibroblastic Reticular Cells and Their Impact on T Cell Response—A Systematic Review

“…The host characteristics in the articles included in this review, such as source, genotype, age, and gender, are described in Table 1 , along with the types and times of interventions used to analyze fibroblastic reticular cell functions. The hosts used in the majority of the studies reviewed here were C57BL/6 mice (79%) [ 18 , 19 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 32 , 33 , 34 , 37 , 38 , 39 , 40 , 41 ]. There were 10 studies (53%) that used some type of genetically modified mice [ 21 , 22 , 25 , 28 , 30 , 32 , 33 , 35 , 38 , 40 ], of which 40% were NOD scid gamma (NSG) mice [ 21 , 25 , 33 , 35 ] and 60% were RAG deficient mice [ 22 , 28 , 30 , 32 , 33 , 35 ].…”

“…The articles reviewed here report on using several animal models of disease and/or genetically modified mice as tools to investigate FRCs’ effect on T cells. These articles also approach and clarify the mechanisms involved in T cell proliferation or differentiation in subsets with regulatory, effector, or memory profiles [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ]. In addition, these articles reported the markers used to identify and isolate FRCs, as well as the methods used for these cells’ cultivation.…”