Project R-14024

IL-34 mediates a novel non-canonical function of regulatory T cells by protecting brain barriers in neuroinflammation (Research)

Disruption of the blood-brain barrier (BBB) is an early and crucial hallmark in the development of the autoimmune disease multiple sclerosis (MS). This event opens a gateway for immune cells into the central nervous system, resulting in demyelination and neurodegeneration. Targeting these barriers has great potential to prevent disease progression. Our preliminary data show that the lack of regulatory T cells (Tregs), mainly known for their immune suppressive function, leads to decreased brain barrier integrity in vivo. We hypothesize that this novel, non-canonical function is mediated by the cytokine IL-34. Indeed, our data show that Tregs produce IL-34, and that this production is decreased in patients with relapsing-remitting MS. Even more, IL-34 protects against brain barrier disruption in several of our in vitro models. Given these preliminary results, we hypothesize that Treg-derived IL-34 protects brain barriers in neuroinflammation. This project will uncover a novel, non-canonical regenerative Treg function related to their production of IL-34, as well as the complete downstream signaling cascade in brain barrier cells. In addition, knowledge will be gained about MS-specific disturbances in the IL-34 response in Tregs. Altogether, harnessing this knowledge will contribute to the development of a long-lasting, reparative Treg-based therapy for MS.

30 June 2023 - 30 August 2024