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

doi:10.1016/j.celrep.2023.113469

PIM kinases regulate early human Th17 cell differentiation

Cell Rep. 2023 Dec 26;42(12):113469. doi: 10.1016/j.celrep.2023.113469. Epub 2023 Nov 30.

Authors

Affiliations

¹ Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland; InFLAMES Research Flagship Center, University of Turku, 20520 Turku, Finland. Electronic address: tanja.buchacher@utu.fi.
² 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.
³ 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.
⁴ Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland; InFLAMES Research Flagship Center, University of Turku, 20520 Turku, Finland.
⁵ Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA 94158, USA; Department of Medicine, University of California San Francisco, San Francisco, CA 94143, USA.
⁶ 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. Electronic address: rilahes@utu.fi.

Abstract

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.

Keywords: CP: Immunology; PIM kinases; T helper cell differentiation; Th1 cells; Th17 cells; bulk RNA sequencing; single-cell RNA sequencing; transcriptomics.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Differentiation
Hematopoiesis
Humans
Mice
Protein Serine-Threonine Kinases* / metabolism
Proto-Oncogene Proteins c-pim-1* / genetics
Proto-Oncogene Proteins c-pim-1* / metabolism
Signal Transduction
Th17 Cells / metabolism

Substances

proto-oncogene proteins pim
Protein Serine-Threonine Kinases
Proto-Oncogene Proteins c-pim-1