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

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

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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.

Original language	English
Article number	113469
Number of pages	19
Journal	Cell Reports
Volume	42
Issue number	12
DOIs	https://doi.org/10.1016/j.celrep.2023.113469
Publication status	Published - 26 Dec 2023
MoE publication type	A1 Journal article-refereed

Keywords

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

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10.1016/j.celrep.2023.113469

1-s2.0-S221112472301481X-mainFinal published version, 5.28 MBLicence: CC BY

https://urn.fi/URN:NBN:fi-fe202402096361

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title = "PIM kinases regulate early human Th17 cell differentiation",

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 = "Animals, Mice, Humans, Protein Serine-Threonine Kinases/metabolism, Proto-Oncogene Proteins c-pim-1/genetics, Signal Transduction, Hematopoiesis, Cell Differentiation, Th17 Cells/metabolism, CP, transcriptomics, single-cell RNA sequencing, bulk RNA sequencing, Th17 cells, Th1 cells, T helper cell differentiation, PIM kinases, Immunology",

author = "Tanja Buchacher and Ankitha Shetty and Koskela, {Saara A} and Johannes Smolander and Riina Kaukonen and Sousa, {Ant{\'o}nio G G} and Sini Junttila and Asta Laiho and Olof Rundquist and Tapio L{\"o}nnberg and Alexander Marson and Omid Rasool and Elo, {Laura L} and Riitta Lahesmaa",

year = "2023",

month = dec,

day = "26",

doi = "10.1016/j.celrep.2023.113469",

language = "English",

volume = "42",

journal = "Cell Reports",

issn = "2211-1247",

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T1 - PIM kinases regulate early human Th17 cell differentiation

AU - Buchacher, Tanja

AU - Shetty, Ankitha

AU - Koskela, Saara A

AU - Smolander, Johannes

AU - Kaukonen, Riina

AU - Sousa, António G G

AU - Junttila, Sini

AU - Laiho, Asta

AU - Rundquist, Olof

AU - Lönnberg, Tapio

AU - Marson, Alexander

AU - Rasool, Omid

AU - Elo, Laura L

AU - Lahesmaa, Riitta

PY - 2023/12/26

Y1 - 2023/12/26

N2 - 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.

AB - 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.

KW - Animals

KW - Mice

KW - Humans

KW - Protein Serine-Threonine Kinases/metabolism

KW - Proto-Oncogene Proteins c-pim-1/genetics

KW - Signal Transduction

KW - Hematopoiesis

KW - Cell Differentiation

KW - Th17 Cells/metabolism

KW - CP

KW - transcriptomics

KW - single-cell RNA sequencing

KW - bulk RNA sequencing

KW - Th17 cells

KW - Th1 cells

KW - T helper cell differentiation

KW - PIM kinases

KW - Immunology

U2 - 10.1016/j.celrep.2023.113469

DO - 10.1016/j.celrep.2023.113469

M3 - Article

C2 - 38039135

SN - 2211-1247

VL - 42

JO - Cell Reports

JF - Cell Reports

IS - 12

M1 - 113469

ER -

PIM kinases regulate early human Th17 cell differentiation

Abstract

Keywords

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