The serine/threonine kinase PIM3 acts as essential gatekeeper of T cell functions 2743
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)
Authors
- Tobias Frey (ORCID: https://orcid.org/0000-0002-6274-9864)
- Lisa E. Wagar (ORCID: https://orcid.org/0000-0001-5980-3586)
- Marlene Hollenstein (ORCID: https://orcid.org/0009-0003-5417-5594)
- Anja Wagner
- Wilfried Ellmeier (ORCID: https://orcid.org/0000-0001-8192-8481)
- Georg Stary (ORCID: https://orcid.org/0000-0003-1746-4250)
- Winfried Franz Pickl (ORCID: https://orcid.org/0000-0003-0430-4952)
- Gottfried Fischer (ORCID: https://orcid.org/0000-0002-3442-3680)
- Franziska Dengler (ORCID: https://orcid.org/0000-0002-2178-2270)
- Tarik Shoumariyeh (ORCID: https://orcid.org/0000-0001-9155-1112)
- Klaus Kratochwill (ORCID: https://orcid.org/0000-0003-0803-614X)
- Marlene C. Gerner (ORCID: https://orcid.org/0000-0002-4378-9254)
- Michael Mildner (ORCID: https://orcid.org/0000-0002-6892-925X)
- Johanna Strobl (ORCID: https://orcid.org/0000-0003-3606-2185)
- Bernhard J. Jank (ORCID: https://orcid.org/0000-0003-1420-5034)
- Lukas Unger (ORCID: https://orcid.org/0000-0002-8423-2268)
- Kamil Mieczkowski (ORCID: https://orcid.org/0000-0003-2996-5861)
- Doris Trapin
- Klaus G. Schmetterer (ORCID: https://orcid.org/0000-0001-9328-4871)
- Ralf Schmidt (ORCID: https://orcid.org/0000-0002-6697-0363)
- Julia Eckl‐Dorna (ORCID: https://orcid.org/0000-0001-5981-1607)
- Nicholas James Campion (ORCID: https://orcid.org/0000-0003-3345-9486)
- Hannes Kühtreiber (ORCID: https://orcid.org/0009-0005-8797-5840)
- K. Schaffer (ORCID: https://orcid.org/0000-0001-5046-9251)
- J Kovarík (ORCID: https://orcid.org/0000-0002-0206-082X)
- Ci Zhu
- Alexandra Tsal-Tsalko
- Simone Allram
- Viola Baur
Institutions
- University of Veterinary Medicine Vienna (AT)
- University of California, Irvine (US)
- Hochschule Campus Wien (AT)
- CeMM Research Center for Molecular Medicine (AT)
- Medical University of Vienna (AT)
Publication Details
- Journal
- The Journal of Immunology
- Published
- 2025-11-01
- DOI
- https://doi.org/10.1093/jimmun/vkaf283.629
- Primary Topic
- Cancer Mechanisms and Therapy
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Austrian Science Fund