Dipeptidyl peptidase-4 inhibitors have adverse effects for the proliferation of human T cells

Noriyuki Kitagawa; Masahide Hamaguchi; Saori Majima; Takuya Fukuda; Toshihiro Kimura; Yoshitaka Hashimoto; Muhei Tanaka; Masahiro Yamazaki; Naoto Nakamura; Michiaki Fukui

doi:10.3164/jcbn.17-64

Original Articles

Dipeptidyl peptidase-4 inhibitors have adverse effects for the proliferation of human T cells

Noriyuki Kitagawa, Masahide Hamaguchi, Saori Majima, Takuya Fukuda, Toshihiro Kimura, Yoshitaka Hashimoto, Muhei Tanaka, Masahiro Yamazaki, Naoto Nakamura, Michiaki Fukui

Author information

Noriyuki Kitagawa
Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine
Masahide Hamaguchi
Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine
Saori Majima
Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine
Takuya Fukuda
Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine
Toshihiro Kimura
Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine
Yoshitaka Hashimoto
Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine
Muhei Tanaka
Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine
Masahiro Yamazaki
Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine
Naoto Nakamura
Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine
Michiaki Fukui
Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine

Keywords: dipeptidyl peptidase-4 inhibitor, human T cell, T cell receptor signaling, immunomodulatory effect

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Supplementary material

2018 Volume 63 Issue 2 Pages 106-112

DOI https://doi.org/10.3164/jcbn.17-64

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Abstract

Dipeptidyl peptidase-4 (DPP-4) is a critical molecule for the metabolism of incretins. In addition, DPP-4 is known as CD26, the receptor of T cells, and plays important role in activation of T cells. Recently, DPP-4 inhibitors (DPP4i) are reported to have several immunologic effects beyond glycemic control. DPP4i seem to have anti-inflammatory effects in patients with type 2 diabetes. This might be direct effects on T cells. However, the close mechanism is not clear. To evaluate the possibility, we performed ex vivo assays by using primarily human CD4⁺ T cells (CD4) and CD8⁺ T cells (CD8). We purified primary naïve CD4 and CD8 from human peripheral blood. Then, we evaluated the effect of DPP4i on the proliferation of naïve T cells and the cytokine production in ex vivo experiments. The proliferation of CD4 and CD8 were suppressed by adding DPP4i in a dose dependent manner. However, DPP4i did not inhibit cytokine production from CD4. It was revealed by phospho-flow that the T cell receptor (TCR) signaling was attenuated in the presence of DPP4i. Taken together, DPP4i modulated TCR signaling, which contributed to attenuate the proliferation of CD4 and CD8. DPP4i have adverse effects for the proliferation of human T cells.

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