IL-34 empowers regulatory T cells with novel non-canonical function to safeguard brain barrier integrity during neuro-inflammation.

In efforts to find reparative strategies for brain damage, brain-associated regulatory T cells (Tregs) have gained increasing attention in recent years. Beyond their textbook immunoregulatory function, Tregs have emerged as key players in the response to brain trauma and the restoration of damaged brain tissue. Here, we are the first to describe a novel, non-canonical function of Tregs in maintaining the sealing capacity of both the blood-brain barrier (BBB) and the blood-cerebrospinal fluid (CSF) barrier. Moreover, we identified the cytokine IL-34 as a critical determinant in this newly unveiled Treg function. Mechanistically, IL-34 exerts its influence by modulating the expression and localization of the tight junction protein ZO-1 in both BBB endothelial cells and choroid plexus epithelial cells, thereby reinforcing the strength of the brain barriers. Given the well-established notion of leaky brain barriers and the involvement of immunological components in neurological diseases such as Alzheimer's disease (AD) and multiple sclerosis (MS), we further demonstrate diminished IL-34 expression in Tregs derived from patients with relapsing-remitting MS (RR-MS) and patients with AD and even mild cognitive impairment (MCI). Remarkably, our study reveals the potential of IL-34 treatment in reinstating the integrity of brain barriers within murine models mimicking these neurological disorders. These ground-breaking findings shed light on the intricate relationship between Tregs, IL-34, and the integrity of brain barriers. They offer novel avenues for therapeutic approaches to ameliorate brain barrier dysfunction in the context of neurological disorders.