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

Natalia B. Pikor, Jillian L. Astarita, Leslie Summers-Deluca, Georgina Galicia, Joy Qu, Lesley A. Ward, Susan Armstrong, Claudia X. Dominguez, Deepali Malhotra, Brendan Heiden, Robert Kay, Valera Castanov, Hanane Touil, Louis Boon, Paul O’Connor, Amit Bar-Or, Alexandre Prat, Valeria Ramaglia, Samuel Ludwin, Shannon J. Turley, Jennifer L. Gommerman

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.