Soluble galectin 9 potently enhanced regulatory T-cell formation, a pathway impaired in patients with intracranial...

Patients with intracranial aneurysm (IA) present a dysregulated immune system with lower frequency of regulatory T (Treg) cells. Here, we examined whether galectin 9 (Gal-9), the natural ligand of Tim-3, could promote Treg cells in IA patients. We first discovered that the intracellular and extracellular Gal-9 was primarily expressed by CD4⁺ CD25^- T conventional (Tconv) cells, and also by monocytes at lower levels, but rarely by CD4⁺ CD25⁺ Treg cells. In IA patients, the Gal-9 expression was significantly lower than in healthy controls. CD4⁺ CD25^- Tconv cells could be induced into Foxp3-expressing induced Treg (iTreg) cells using a TGF-β-containing milieu. We found that soluble Gal-9 significantly enhanced this process by potently upregulating the expression of Foxp3, IL-10 and TGF-β in a concentration-dependent manner. In addition, in the absence of additional Gal-9, the level of Foxp3 upregulation was directly correlated with the level of intrinsic Gal-9 expression. Notably, the strength of external Gal-9-mediated effects was significantly lower in IA patients than in healthy controls. Using a Tim-3 blocking antibody, we found that the promotion of iTreg development by soluble Gal-9 was dependent on the Tim-3 signalling pathway. Overall, our investigations demonstrated that Gal-9 presented a critical role in the development of iTreg cells. However, this mechanism was impaired in IA patients due to lower expression of both Gal-9 and Tim-3.