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

Abstract

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.

Tertiary Lymphoid Organs in Central Nervous System Autoimmunity

“…Following adoptive transfer of either MOG-specific Th17 cells in the C57Bl/6 background or PLP-specific Th17 cells in the SJL background, TLOs were identified with relatively high frequency in the CNS of sick mice (75, 76). …”

“…Thus, both in the SJL immunization model as well as after transfer of Th17 cells on the SJL background, TLOs form primarily in the brain meninges, particularly those lining brainstem and ventricles (70, 71, 76). Similarly, in the MP4 immunization model TLOs form in the cerebral periventricular space, but also in the cerebellum and in association with spinal meninges (72).…”

“…In EAE TLOs, reticulin fibers suggestive of stromal FRC-like cells were described in several models, including the MP4-immunization model, the spontaneous OSE model, and the Th17 transfer model (C57Bl/6) (72, 73, 75). In a more detailed analysis, Pikor and colleagues could show that the fraction of FRC-like meningeal fibroblasts, which express Pdpn, PDGFRα, PDGFRβ, and Cadherin11 on their surface and secrete ECM components including fibronectin and ERTR7, increases during CNS inflammation (76). Therefore, the relative abundance of fibroblasts in the meninges, which can be stimulated to adopt FRC-like phenotype and function, may partly explain why TLOs are predominantly located in the meninges.…”

“…Thus, absence of FDCs in the spontaneous OSE model and Th17 transfer models might be caused by lack of appropriate FDC maturation signals or by lack of time leading to an incomplete differentiation process. The latter may be especially true for the Th17 transfer models, where mice were analyzed comparatively early (5–20 days post onset) to prevent extended suffering due to severity of disease (75, 76). On the other hand, it is also unclear whether FDCs are required for antigen presentation in germinal center reactions in TLOs.…”

Gel-Trapped Lymphorganogenic Chemokines Trigger Artificial Tertiary Lymphoid Organs and Mount Adaptive Immune Responses In Vivo

“…The TLOs also showed PNAd positive HEVs and lymphatic vessels (19–21). Mice expressing CXCL13 under the control of RIP also developed TLOs with distinct B cell follicles and T cell areas in the pancreas (4, 22).…”