Abstract：
:Inhibitory receptors (IRs) function as critical regulators of immune responses by tempering T cell activity. In humans, several persisting viruses as well as cancers exploit IR signaling by upregulating IR ligands, resulting in suppression of T cell function (i.e., exhaustion). This allows escape from immune surveillance and continuation of disease. Here, we report the design, implementation, and results of a phenotypic high-throughput screen for molecules that modulate CD8+ T cell activity. We identify 19 compounds from the ReFRAME drug-repurposing collection that restore cytokine production and enhance the proliferation of exhausted T cells. Analysis of our top hit, ingenol mebutate, a protein kinase C (PKC) inducing diterpene ester, reveals a role for this molecule in overriding the suppressive signaling cascade mediated by IR signaling on T cells. Collectively, these results demonstrate a disease-relevant methodology for identifying modulators of T cell function and reveal new targets for immunotherapy.
journal_name
Cell Repjournal_title
Cell reportsauthors
Marro BS,Zak J,Zavareh RB,Teijaro JR,Lairson LL,Oldstone MBAdoi
10.1016/j.celrep.2019.10.119subject
Has Abstractpub_date
2019-12-03 00:00:00pages
3293-3302.e3issue
10issn
2211-1247pii
S2211-1247(19)31452-4journal_volume
29pub_type
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