Progenitor-like CD8 + T cells mediate long-term immunity to chronic infection and cancer and respond potently to immune checkpoint blockade. These cells share transcriptional regulators with memory precursor cells, including TCF1, but it is unclear whether they adopt distinct programs to adapt to the immunosuppressive environment. By comparing single-cell transcriptomes and epigenetic profiles of CD8 + T cells responding to acute and chronic viral infections, we found that progenitor-like CD8 + T cells became distinct from memory precursors before the peak of the T-cell response. We discovered a co-expression gene module containing Tox that exhibited higher transcriptional activity associated with more abundant active histone marks in progenitor-like cells than memory precursors. Moreover, TOX promoted persistence of antiviral CD8 + T cells and was required for the programming of progenitor-like CD8 + T cells. Thus, long-term CD8 + T-cell immunity to chronic viral infection requires unique transcriptional and epigenetic programs associated with the transcription factor TOX.

Microglia are the resident inflammatory cells of the central nervous system (CNS) and have important roles in development, homeostasis and a variety of neurologic and psychiatric diseases. Difficulties in procuring human microglia have limited their study and hampered the clinical translation of microglia-based treatments shown to be effective in animal disease models. Here, we report the differentiation of human induced pluripotent stem cells (iPSC) into microglia-like cells by exposure to defined factors and co-culture with astrocytes. These iPSC-derived microglia (iPS-MG) have the phenotype, gene expression profile and functional properties of brain-isolated microglia. Murine iPS-MG generated using a similar protocol have equivalent efficacy to primary brain-isolated microglia in the treatment of murine syngeneic intracranial malignant gliomas. The ability to generate human microglia facilitates the further study of this important CNS cell type and raises the possibility of their use in personalized medicine applications.

and that therapeutic blockade of these pathways either before or during persistent infection can promote viral clearance. Transforming growth factor beta (TGF-␤) is another immunosuppressive cytokine known to impede both self-and tumor-specific T cells, but its role in regulating antiviral immunity is not entirely understood. In this study, we inhibited TGF-␤ with three potent antagonists to determine whether neutralization of this regulatory molecule is a viable approach to control a persistent viral infection. Our results revealed that these inhibitors modestly elevate the number of antiviral T cells following infection with a persistent variant of lymphocytic choriomeningitis virus (LCMV) but have no impact on viral clearance. These data suggest that therapeutic neutralization of TGF-␤ is not an efficacious means to promote clearance of a persistent viral infection.