PIM kinases regulate early human Th17 cell differentiation
Tanja Buchacher,
Ankitha Shetty,
Saara A. Koskela,
Johannes Smolander,
Riina Kaukonen,
António G.G. Sousa,
Sini Junttila,
Asta Laiho,
Olof Rundquist,
Tapio Lönnberg,
Alexander Marson,
Omid Rasool,
Laura L. Elo,
Riitta Lahesmaa
Affiliations
Tanja Buchacher
Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland; InFLAMES Research Flagship Center, University of Turku, 20520 Turku, Finland; Corresponding author
Ankitha Shetty
Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland; InFLAMES Research Flagship Center, University of Turku, 20520 Turku, Finland; Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA 94143, USA
Saara A. Koskela
Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland; InFLAMES Research Flagship Center, University of Turku, 20520 Turku, Finland; Institute of Biomedicine, University of Turku, 20520 Turku, Finland
Johannes Smolander
Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland; InFLAMES Research Flagship Center, University of Turku, 20520 Turku, Finland
Riina Kaukonen
Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland; InFLAMES Research Flagship Center, University of Turku, 20520 Turku, Finland
António G.G. Sousa
Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland; InFLAMES Research Flagship Center, University of Turku, 20520 Turku, Finland
Sini Junttila
Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland; InFLAMES Research Flagship Center, University of Turku, 20520 Turku, Finland
Asta Laiho
Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland; InFLAMES Research Flagship Center, University of Turku, 20520 Turku, Finland
Olof Rundquist
Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland; InFLAMES Research Flagship Center, University of Turku, 20520 Turku, Finland
Tapio Lönnberg
Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland; InFLAMES Research Flagship Center, University of Turku, 20520 Turku, Finland
Alexander Marson
Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA 94158, USA; Department of Medicine, University of California San Francisco, San Francisco, CA 94143, USA
Omid Rasool
Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland; InFLAMES Research Flagship Center, University of Turku, 20520 Turku, Finland
Laura L. Elo
Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland; InFLAMES Research Flagship Center, University of Turku, 20520 Turku, Finland; Institute of Biomedicine, University of Turku, 20520 Turku, Finland
Riitta Lahesmaa
Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland; InFLAMES Research Flagship Center, University of Turku, 20520 Turku, Finland; Institute of Biomedicine, University of Turku, 20520 Turku, Finland; Corresponding author
Summary: The serine/threonine-specific Moloney murine leukemia virus (PIM) kinase family (i.e., PIM1, PIM2, and PIM3) has been extensively studied in tumorigenesis. PIM kinases are downstream of several cytokine signaling pathways that drive immune-mediated diseases. Uncontrolled T helper 17 (Th17) cell activation has been associated with the pathogenesis of autoimmunity. However, the detailed molecular function of PIMs in human Th17 cell regulation has yet to be studied. In the present study, we comprehensively investigated how the three PIMs simultaneously alter transcriptional gene regulation during early human Th17 cell differentiation. By combining PIM triple knockdown with bulk and scRNA-seq approaches, we found that PIM deficiency promotes the early expression of key Th17-related genes while suppressing Th1-lineage genes. Further, PIMs modulate Th cell signaling, potentially via STAT1 and STAT3. Overall, our study highlights the inhibitory role of PIMs in human Th17 cell differentiation, thereby suggesting their association with autoimmune phenotypes.
