Integration of Th17- and Lymphotoxin-Derived Signals Initiates Meningeal-Resident Stromal Cell Remodeling to Propagate Neuroinflammation

• Published in: Immunity (Cambridge, Mass.) Mass.), 2015-12, Vol.43 (6), p.1160-1173
• Main Authors: Pikor, Natalia B., Astarita, Jillian L., Summers-Deluca, Leslie, Galicia, Georgina, Qu, Joy, Ward, Lesley A., Armstrong, Susan, Dominguez, Claudia X., Malhotra, Deepali, Heiden, Brendan, Kay, Robert, Castanov, Valera, Touil, Hanane, Boon, Louis, O’Connor, Paul, Bar-Or, Amit, Prat, Alexandre, Ramaglia, Valeria, Ludwin, Samuel, Turley, Shannon J., Gommerman, Jennifer L.
• Format: Article
• Language: English
• Subjects: Adult; Animals; Antigens; Brain research; CD4-Positive T-Lymphocytes - immunology; Dendritic cells; Disease; Encephalomyelitis, Autoimmune, Experimental - immunology; Encephalomyelitis, Autoimmune, Experimental - pathology; Female; Flow Cytometry; Humans; Immunoglobulins; Immunohistochemistry; Inflammation; Inflammation - immunology; Lymphocytes; Lymphotoxin-alpha - immunology; Male; Meninges - cytology; Meninges - immunology; Mice; Mice, Knockout; Multiple Sclerosis, Relapsing-Remitting - immunology; Polymerase Chain Reaction; Scholarships & fellowships; Signal Transduction - immunology; Stromal Cells - immunology; Th17 Cells - immunology; Tumor necrosis factor-TNF
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2015.11.010

Tertiary lymphoid tissues (TLTs) have been observed in the meninges of multiple sclerosis (MS) patients, but the stromal cells and molecular signals that support TLTs remain unclear. Here, we show that T helper 17 (Th17) cells induced robust TLTs within the brain meninges that were associated with local demyelination during experimental autoimmune encephalitis (EAE). Th17-cell-induced TLTs were underpinned by a network of stromal cells producing extracellular matrix proteins and chemokines, enabling leukocytes to reside within, rather than simply transit through, the meninges. Within the CNS, interactions between lymphotoxin αβ (LTαβ) on Th17 cells and LTβR on meningeal radio-resistant cells were necessary for the propagation of de novo interleukin-17 responses, and activated T cells from MS patients expressed elevated levels of LTβR ligands. Therefore, input from both Th17 cells and the lymphotoxin pathway induce the formation of an immune-competent stromal cell niche in the meninges. [Display omitted] •A fibroblastic reticular cell (FRC) network forms in the meninges during EAE•Meningeal FRCs express cytokines and chemokines during EAE•Inhibition of IL-17 and IL-22 in the CNS short circuits FRC remodeling•LTβR+ radio-resistant cells promote T cell cytokine production in the CNS Tertiary lymphoid tissues (TLTs) have been noted in chronically inflamed tissues, including the brain meninges, but the nature of the stromal cells that support meningeal TLTs is unclear. Gommerman and colleagues characterized stromal cells in the inflamed meninges and found that the Th17 cell and lymphotoxin pathways collaborate to form TLTs.