IFN-γ and proinflammatory cytokines induce astrocyte programs that support antigen-dependent CD4⁺ T cell restimulation

Astrocyte contributions to CNS antigen presentation remain poorly defined. We show that interferon gamma (IFN-γ, the sole type II interferon), with proinflammatory cytokines, induces astrocytes to express components mediating attraction of and antigen presentation to CD4⁺ T cells. Re-analysis of astrocyte-enriched single-cell sequencing from bacterial mimetic-injected mice revealed a transcriptionally distinct, IFN-responsive astrocyte population enriched for antigen-presentation genes 24 h after peripheral immune challenge. In vivo, type II major histocompatibility complex (MHC-II⁺)GFAP⁺ astrocytes localize to the brain surface across multiple mouse models of neuroinflammation and in human neurological disease tissue. In vitro, purified astrocytes stimulated with IFN-γ and proinflammatory cytokines expressed MHC-II, costimulatory molecules, and lymphocyte-recruiting chemokines, and in co-culture supported rapid antigen-dependent expansion of previously activated CD4⁺ T cells. Human iPSC-derived CNS cultures showed equivalent induction of antigen-presentation machinery in human astrocytes following inflammatory cytokine stimulation. These findings define a cytokine-induced astrocyte state expressing antigen-presentation machinery at neuroimmune interfaces that can support local CD4⁺ T cell responses.