IFNγ and proinflammatory cytokines cooperatively license astrocytes to support antigen-dependent CD4+ T cell restimulation

Fisher, T. M.; Limone, F.; Smith, M. D.; Wright, C.; Kukanja, P.; Lu, P.; Limberg, K.; Pirjanian, N.; Zulueta, J.; Fossati, V.; Iwasaki, A.; Calabresi, P. A.; Liddelow, S. A.

doi:10.64898/2026.07.29.741554

bioRxiv · 10.64898/2026.07.29.741554

IFNγ and proinflammatory cytokines cooperatively license astrocytes to support antigen-dependent CD4+ T cell restimulation

Fisher, T. M.·Limone, F.·Smith, M. D.·Wright, C.·Kukanja, P.·Lu, P.·Limberg, K.·Pirjanian, N.·Zulueta, J.·Fossati, V.·Iwasaki, A.·Calabresi, P. A.·Liddelow, S. A.

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Abstract

We report that type 2 interferon with proinflammatory cytokines induces astrocytes to express multiple components required for attraction of and antigen presentation to CD4+ T cells via MHC-II molecules. Re-analysis of astrocyte-enriched single-cell sequencing from bacterial mimetic-injected mice revealed a transcriptionally distinct interferon-responsive astrocyte population enriched for antigen-presentation-associated genes 24 hours after peripheral immune challenge. In vivo, we identify MHC-II+GFAP+ astrocytes localized to the surface of the brain across multiple mouse models of neuroinflammation and in human neurological disease tissue. In a pure in vitro culture system, astrocytes stimulated with IFN{gamma} and proinflammatory cytokines express MHC-II, costimulatory molecules and lymphocyte-recruiting chemokines, and support rapid antigen-dependent expansion of previously activated CD4+ T cells. Using human iPSC-derived CNS cultures, we additionally show induction of antigen-presentation-associated machinery in human astrocytes following inflammatory cytokine stimulation. Rather than inferring function solely from marker expression, we assessed astrocyte-supported T cell restimulation in vitro and separately characterized the emergence of antigen-presentation-associated astrocytes in vivo at neuroimmune interfaces during inflammation in mice and humans. Together, these findings support a conserved role for cytokine-stimulated astrocytes in expressing antigen-presentation-associated machinery and, in vitro, supporting antigen-dependent restimulation/expansion of CD4+ T cells under inflammatory conditions.

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Fisher, T. M., Limone, F., Smith, M. D., Wright, C., Kukanja, P., Lu, P., Limberg, K., Pirjanian, N., Zulueta, J., Fossati, V., Iwasaki, A., Calabresi, P. A., Liddelow, S. A.. 2026-08-04. IFNγ and proinflammatory cytokines cooperatively license astrocytes to support antigen-dependent CD4+ T cell restimulation. https://doi.org/10.64898/2026.07.29.741554

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