MAP4K4 deletion inhibits proliferation and activation of CD4(+) T cell and promotes T regulatory cell generation in vitro

Hongpeng Huang; Qiuqiong Tang; Hongqian Chu; Jianjun Jiang; Haizhou Zhang; Weidong Hao; Xuetao Wei

doi:10.1016/j.cellimm.2014.02.006

MAP4K4 deletion inhibits proliferation and activation of CD4(+) T cell and promotes T regulatory cell generation in vitro

Cell Immunol. 2014 May-Jun;289(1-2):15-20. doi: 10.1016/j.cellimm.2014.02.006. Epub 2014 Mar 11.

Authors

Hongpeng Huang¹, Qiuqiong Tang¹, Hongqian Chu¹, Jianjun Jiang¹, Haizhou Zhang², Weidong Hao³, Xuetao Wei⁴

Affiliations

¹ Department of Toxicology, School of Public Health, Peking University, Beijing 100191, PR China; Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, Peking University Health Science Center, Beijing 100191, PR China.
² Roche R&D Center (China) Ltd., Shanghai 201203, PR China.
³ Department of Toxicology, School of Public Health, Peking University, Beijing 100191, PR China; Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, Peking University Health Science Center, Beijing 100191, PR China. Electronic address: [email protected].
⁴ Department of Toxicology, School of Public Health, Peking University, Beijing 100191, PR China; Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, Peking University Health Science Center, Beijing 100191, PR China. Electronic address: [email protected].

PMID: 24681727
DOI: 10.1016/j.cellimm.2014.02.006

Abstract

CD4(+) T cells are critical for adaptive immunity. MAP4K4 is a key member of germinal center kinase group. However, the physiological function of MAP4K4 in primary CD4(+) T cells is still unclear. In this study, it was demonstrated that in vitro, MAP4K4 deletion remarkably suppressed CD4(+) T cell proliferation in response to phorbol 12-myristate 13-acetate (PMA) and ionomycin, which was not due to enhancing cell apoptosis. Additionally, MAP4K4 was required for the activation of CD4(+) T cells. MAP4K4 deletion significantly down-regulated expression of interleukin 2 (IL-2) and interferon-γ (IFN-γ), while notably up-regulating the expression of regulatory T cells (Treg) transcription factor Foxp3 in peripheral CD4(+) T cells. Furthermore, western blot analysis indicated that CD4(+) T cells lacking MAP4K4 failed to phosphorylate Jnk, Erk, p38 and PKC-θ. Thus, our results provide the evidence that MAP4K4 is essential for CD4(+) T cell proliferation, activation and cytokine production.

Keywords: CD4(+) T cells; MAP4K4; PKC-θ; Treg.

MeSH terms

Animals
Cell Differentiation / genetics
Cell Differentiation / immunology
Cell Proliferation
Cells, Cultured
Down-Regulation
Enzyme Activation / genetics
Enzyme Activation / immunology
Extracellular Signal-Regulated MAP Kinases / metabolism
Forkhead Transcription Factors / biosynthesis
Gene Deletion
Interferon-gamma / biosynthesis
Interleukin-2 / biosynthesis
Ionomycin
Isoenzymes / metabolism*
JNK Mitogen-Activated Protein Kinases / metabolism
Lymphocyte Activation / genetics*
Lymphocyte Activation / immunology
Mice
Mice, Inbred C57BL
Mice, Transgenic
NF-kappaB-Inducing Kinase
Phosphorylation / genetics
Protein Kinase C / metabolism*
Protein Kinase C-theta
Protein Serine-Threonine Kinases / genetics*
T-Lymphocytes, Regulatory / immunology*
Tetradecanoylphorbol Acetate
p38 Mitogen-Activated Protein Kinases / metabolism

Substances

Forkhead Transcription Factors
Foxp3 protein, mouse
Interleukin-2
Isoenzymes
Ionomycin
Interferon-gamma
Protein Serine-Threonine Kinases
Prkcq protein, mouse
Protein Kinase C
Protein Kinase C-theta
Extracellular Signal-Regulated MAP Kinases
JNK Mitogen-Activated Protein Kinases
p38 Mitogen-Activated Protein Kinases
Tetradecanoylphorbol Acetate