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The limited efficacy of immunotherapies against glioblastoma underscores the urgency of better understanding immunity in the central nervous system. We found that treatment with αCTLA-4, but not αPD-1, prolonged survival in a mouse model of mesenchymal-like glioblastoma. This effect was lost upon the depletion of CD4+ T cells but not CD8+ T cells. αCTLA-4 treatment increased frequencies of intratumoral IFNγ-producing CD4+ T cells, and IFNγ blockade negated the therapeutic impact of αCTLA-4. The anti-tumor activity of CD4+ T cells did not require tumor-intrinsic MHC-II expression but rather required conventional dendritic cells as well as MHC-II expression on microglia. CD4+ T cells interacted directly with microglia, promoting IFNγ-dependent microglia activation and phagocytosis via the AXL/MER tyrosine kinase receptors, which were necessary for tumor suppression. Thus, αCTLA-4 blockade in mesenchymal-like glioblastoma promotes a CD4+ T cell-microglia circuit wherein IFNγ triggers microglia activation and phagocytosis and microglia in turn act as antigen-presenting cells fueling the CD4+ T cell response. [Display omitted] • αCTLA-4 therapy induces protective CD4+ Th1 cells against mesenchymal glioblastomas • Th1-derived IFNγ induces MHC-II+ microglia that sustains Th1 anti-glioma immunity • Th1 cells promote microglia phagocytosis of gliomas via AXL-MER receptor signaling • Microglia and MHC-II expression are protective correlates in human glioblastoma Immunotherapies against glioblastoma exhibit limited efficacy. Chen et al. examine the impact of immunotherapy in mesenchymal glioblastomas and find that αCTLA-4 treatment promotes tumor suppression in a manner dependent on CD4+ T cells. Mechanistically, microglia serve as essential MHC-II antigen-presenting cells that sustain anti-tumor IFNγ+ CD4+ T cells, which in turn stimulate microglial phagocytic function via AXL-MER signaling. [ABSTRACT FROM AUTHOR]

CD8+ T cells provide host protection against pathogens by differentiating into distinct effector and memory cell subsets, but how chromatin is site-specifically remodeled during their differentiation is unclear. Due to its critical role in regulating chromatin and enhancer accessibility through its nucleosome remodeling activities, we investigated the role of the canonical BAF (cBAF) chromatin remodeling complex in antiviral CD8+ T cells during infection. ARID1A, a subunit of cBAF, was recruited early after activation and established de novo open chromatin regions (OCRs) at enhancers. Arid1a deficiency impaired the opening of thousands of activation-induced enhancers, leading to loss of TF binding, dysregulated proliferation and gene expression, and failure to undergo terminal effector differentiation. Although Arid1a was dispensable for circulating memory cell formation, tissue-resident memory (Trm) formation was strongly impaired. Thus, cBAF governs the enhancer landscape of activated CD8+ T cells that orchestrates TF recruitment and activity and the acquisition of specific effector and memory differentiation states. [Display omitted] • ARID1A-containing cBAF opens enhancers in effector CD8+ T cells during infection • cBAF establishes binding sites of many effector TFs, including T-bet and BATF • cBAF is necessary for late-stage differentiation of TE and Trm cells • Circulating memory cells form without cBAF, but are functionally impaired Chromatin remodeling is a critical step for cellular differentiation. McDonald et al. show that the canonical BAF complex mediates chromatin remodeling to establish de novo enhancers in recently activated virus-specific CD8+ T cells, which, in turn, allows the activated cells to acquire specialized effector and memory cell fates. [ABSTRACT FROM AUTHOR]