The serine/threonine kinase PIM3 acts as essential gatekeeper of T cell functions 2743

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Abstract Description Intracellular signaling factors are important targets for immunosuppressive drugs. We report a selective induction of the serine/threonine kinase Provirus Integration site for Moloney murine leukemia virus 3 (PIM3), but not its homologs PIM1 and PIM2, in activated human T cells. Specific pharmacological inhibition and CRISPR/Cas9-mediated knockout of PIM3 in primary human T cells within 2D and 3D cell culture models uncovered essential roles of this kinase in regulating T cell proliferation, viability, migration, metabolic activity, and cytotoxicity. Furthermore, PIM3 inhibition resulted in immunosuppressive effects in human immune organoids. Mass spectrometry-based target protein identification coupled with genome engineering revealed that PIM3 targets the Nucleolar protein Interacting with the FHA domain of MKI67 (NIFK) to control T cell proliferation, establishing a novel regulatory circuit that could be targeted therapeutically in conditions involving T cell hyperproliferation. Elevated PIM3 expression was detected in pathologic T cell infiltrates in human patients and pre-clinical models. Together, these findings identify PIM3 as a promising new target for immunosuppressive therapies. Funding Sources Supported by the Austrian Science Funds (FWF) project P34728-B Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)

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