Tim-3 is a T helper type 1 (T(H)1)-specific cell surface molecule that seems to regulate T(H)1 responses and the induction of peripheral tolerance. However, the identity of the Tim-3 ligand and the mechanism by which this ligand inhibits the function of effector T(H)1 cells remain unknown. Here we show that galectin-9 is the Tim-3 ligand. Galectin-9-induced intracellular calcium flux, aggregation and death of T(H)1 cells were Tim-3-dependent in vitro, and administration of galectin-9 in vivo resulted in selective loss of interferon-gamma-producing cells and suppression of T(H)1 autoimmunity. These data suggest that the Tim-3-galectin-9 pathway may have evolved to ensure effective termination of effector T(H)1 cells.

Foxp3 is a key transcription factor involved in the generation and function of regulatory T (Treg) cells. Transforming growth factor β (TGF-β) induces Foxp3, which generates inducible Foxp3+ Treg cells from naïve T cells, and interleukin 6 (IL-6) inhibits the generation of inducible Treg cells and induces T helper cells that produce IL-17 (TH-17 cells). However, a role for IL-4 in the generation of TGF-β-induced Treg cells and/or the generation of effector CD4+ T helper cells has not been studied. Here, we show that IL-4 blocked the generation of TGF-β-induced Foxp3+ Treg cells. Instead, IL-4 induced a population of T helper cells that predominantly produce IL-9 and IL-10. The IL-9+IL-10+ T cells did not exhibit any regulatory properties in spite of producing large quantities of IL-10. Adoptive transfer of IL-9+IL-10+producing T cells into RAG-1-deficient mice induced colitis and peripheral neuritis. Interestingly, the severity of tissue inflammation was aggravated when IL-9+IL-10+ T cells were co-transferred with CD45RBhi CD4+ effector T cells into RAG-1-deficient mice, which indicated that IL-9+IL-10+ T cells do not display any suppressive function and therefore constitute a unique population of IL-10-producing helper-effector T cells that promote tissue inflammation.

Migration toward pathology is the first critical step in stem cell engagement during regeneration. Neural stem cells (NSCs) migrate through the parenchyma along nonstereotypical routes in a precise directed manner across great distances to injury sites in the CNS, where they might engage niches harboring local transiently expressed reparative signals. The molecular mechanisms for NSC mobilization have not been identified. Because NSCs seem to home similarly to pathologic sites derived from disparate etiologies, we hypothesized that the inflammatory response itself, a characteristic common to all, guides the behavior of potentially reparative cells. As proof of concept, we show that human NSCs migrate in vivo (including from the contralateral hemisphere) toward an infarcted area (a representative CNS injury), where local astrocytes and endothelium up-regulate the inflammatory chemoattractant stromal cell-derived factor 1␣ (SDF-1␣). NSCs express CXC chemokine receptor 4 (CXCR4), the cognate receptor for SDF-1␣. Exposure of SDF-1␣ to quiescent NSCs enhances proliferation, promotes chain migration and transmigration, and activates intracellular molecular pathways mediating engagement. CXCR4 blockade abrogates their pathology-directed chain migration, a developmentally relevant mode of tangential migration that, if recapitulated, could explain homing along nonstereotypical paths. Our data implicate SDF-1␣͞CXCR4, representative of the inflammatory milieu characterizing many pathologies, as a pathway that activates NSC molecular programs during injury and suggest that inflammation may be viewed not simply as playing an adverse role but also as providing stimuli that recruit cells with a regenerative homeostasis-promoting capacity. CXCR4 expression within germinal zones suggests that NSC homing after injury and migration during development may invoke similar mechanisms.human stem cells ͉ homing ͉ chain migration ͉ stroke ͉ hypoxia-ischemia