Astrocyte-Regulatory T Cell Communication in Neuroinflammation: From Glial Reactivity to Immune Modulation

The interaction between astrocytes, microglia, and regulatory T cells (Tregs) is essential for maintaining immune homeostasis in the central nervous system (CNS). During neuroinflammation, communication between astrocytes and reactive microglia promotes the upregulation of chemokines that induce T cell infiltration and differentiation into Th17 cells through RORγt activation in response to IL-1β. Effector Th17 cells secrete IL-17 A and IL-17 F, which act on astrocytes and reactive microglia to induce the secondary release of TNF-α and IL-6. This establishes a paracrine feed-forward loop in which glia-derived IL-6 promotes further polarization of T cells toward the Th17 phenotype. In turn, TNF-α acts synergistically with IL-17 to promote the expansion of neurotoxic reactive astrocytes and contributes to disease progression. In contrast, sustained pro-inflammatory cytokine signaling induces CD69 expression on T cells, which, upon interaction with the S100A8/A9 complex secreted by reactive astrocytes, suppresses RORγt and promotes the generation of immunoregulatory Tregs. These CD69⁺ Tregs secrete IL-10 and amphiregulin (Areg), attenuating astrogliosis by inhibiting the STAT3-IL-6 pathway and helping to restore cerebral homeostasis. The persistence and dynamic regulation of Tregs underscore their homeostatic and therapeutic relevance. Additionally, communication between the gut microbiota (GM) and the aryl hydrocarbon receptor (AhR) is a key modulator of the Th17/Treg axis. Although its role in T cell differentiation within the CNS still requires further investigation, it represents a promising therapeutic strategy to modulate glial activation in chronic neuroinflammatory diseases.