Meningeal mast cell-T cell crosstalk regulates T cell encephalitogenicity

• GM-CSF expression by myelin-specific T cells orchestrates neuroinflammation in EAE.
• IL-1β is essential for promoting pathogenic GM-CSF expression by T cells.
• Meningeal mast cells are a critical source of IL-1β in early EAE.
• Meningeal mast cell: T cell interactions license pathogenic T cells in EAE.
• Mast cells and T cells co-localize in the meninges of a subset of acute MS patients.

GM-CSF is a cytokine produced by T helper (Th) cells that plays an essential role in orchestrating neuroinflammation in experimental autoimmune encephalomyelitis, a rodent model of multiple sclerosis. Yet where and how Th cells acquire GM-CSF expression is unknown. In this study we identify mast cells in the meninges, tripartite tissues surrounding the brain and spinal cord, as important contributors to antigen-specific Th cell accumulation and GM-CSF expression. In the absence of mast cells, Th cells do not accumulate in the meninges nor produce GM-CSF. Mast cell-T cell co-culture experiments and selective mast cell reconstitution of the meninges of mast cell-deficient mice reveal that resident meningeal mast cells are an early source of caspase-1-dependent IL-1β that licenses Th cells to produce GM-CSF and become encephalitogenic. We also provide evidence of mast cell-T cell co-localization in the meninges and CNS of recently diagnosed acute MS patients indicating similar interactions may occur in human demyelinating disease.