PI3K-Akt pathway enhances the differentiation of interleukin-27-induced type 1 regulatory T cells

Niken Adiba Nadya; Hiroyuki Tezuka; Toshiaki Ohteki; Satoshi Matsuda; Miyuki Azuma; Shigenori Nagai

doi:10.1111/imm.12789

PI3K-Akt pathway enhances the differentiation of interleukin-27-induced type 1 regulatory T cells

Immunology. 2017 Nov;152(3):507-516. doi: 10.1111/imm.12789. Epub 2017 Jul 31.

Authors

Niken Adiba Nadya¹, Hiroyuki Tezuka^{2

3}, Toshiaki Ohteki³, Satoshi Matsuda⁴, Miyuki Azuma¹, Shigenori Nagai¹

Affiliations

¹ Department of Molecular Immunology, Graduate School, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.
² Life Science Tokyo Advanced Research Centre, School of Pharmacy and Pharmaceutical Sciences, Hoshi University, Shinagawa-ku, Tokyo, Japan.
³ Department of Biodefence, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.
⁴ Department of Cell Signalling, Institute of Biomedical Science, Kansai Medical University, Moriguchi, Osaka, Japan.

Abstract

Interleukin 27 (IL-27) has been identified as a potent cytokine in the differentiation of type 1 regulatory T (Tr1) cells through interactions with several key elements, including transcription factors such as aryl hydrocarbon receptor and IL-21. Autocrine production of IL-21 is known to be important for maintaining IL-10 expression by Tr1 cells. Although previous studies have shown that the phosphoinositide 3-kinase (PI3K) -Akt axis contributes to the differentiation of helper T-cell subsets, the role of the PI3K pathway on Tr1 cell differentiation remains to be elucidated. Here, we demonstrate that suppression of the PI3K-Akt pathway results in impairment of IL-27-induced Tr1 (IL-27-Tr1) cell differentiation in vitro and in vivo. Furthermore, this suppression down-regulates IL-21 receptor expression by Tr1 cells, followed by suppression of IL-10 expression by IL-27-Tr1 cells. These results suggest that the PI3K pathway enhances IL-10 expression by IL-27-Tr1 cells through up-regulation of IL-21 receptors.

Keywords: interleukin-21 receptor; interleukin-27; phosphoinositide 3-kinase; type 1 regulatory T cells.

MeSH terms

Animals
Cell Differentiation / drug effects*
Cells, Cultured
Female
Forkhead Box Protein O1 / immunology
Forkhead Box Protein O1 / metabolism
Forkhead Transcription Factors / genetics
Forkhead Transcription Factors / metabolism
Genotype
Interleukin-10 / genetics
Interleukin-10 / metabolism
Interleukin-21 Receptor alpha Subunit / immunology
Interleukin-21 Receptor alpha Subunit / metabolism
Interleukin-27 / pharmacology*
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Transgenic
Phenotype
Phosphatidylinositol 3-Kinase / metabolism*
Phosphoinositide-3 Kinase Inhibitors
Phosphorylation
Protein Kinase Inhibitors / pharmacology
Proto-Oncogene Proteins c-akt / genetics
Proto-Oncogene Proteins c-akt / metabolism*
Signal Transduction / drug effects*
T-Lymphocytes, Regulatory / drug effects*
T-Lymphocytes, Regulatory / immunology
T-Lymphocytes, Regulatory / metabolism

Substances

Forkhead Box Protein O1
Forkhead Transcription Factors
Foxo1 protein, mouse
Foxp3 protein, mouse
IL10 protein, mouse
Il21r protein, mouse
Interleukin-21 Receptor alpha Subunit
Interleukin-27
Phosphoinositide-3 Kinase Inhibitors
Protein Kinase Inhibitors
Interleukin-10
Phosphatidylinositol 3-Kinase
Proto-Oncogene Proteins c-akt