The kinase PDK1 is critical for promoting T follicular helper cell differentiation.

Zhen Sun,Yingpeng Yao,Shuyang Yu,Fang Wang,Menghao You,Weiping Yuan,Wenhui Guo,Zhihong Qi,Zhao Wang,Jingjing Liu

doi:10.7554/elife.61406

Zhen Sun, Yingpeng Yao + Show 8 more

Open Access

https://doi.org/10.7554/elife.61406

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Abstract

The kinase PDK1 is a crucial regulator for immune cell development by connecting PI3K to downstream AKT signaling. However, the roles of PDK1 in CD4+ T cell differentiation, especially in T follicular helper (Tfh) cell, remain obscure. Here we reported PDK1 intrinsically promotes the Tfh cell differentiation and germinal center responses upon acute infection by using conditional knockout mice. PDK1 deficiency in T cells caused severe defects in both early differentiation and late maintenance of Tfh cells. The expression of key Tfh regulators was remarkably downregulated in PDK1-deficient Tfh cells, including Tcf7, Bcl6, Icos, and Cxcr5. Mechanistically, ablation of PDK1 led to impaired phosphorylation of AKT and defective activation of mTORC1, resulting in substantially reduced expression of Hif1α and p-STAT3. Meanwhile, decreased p-AKT also suppresses mTORC2-associated GSK3β activity in PDK1-deficient Tfh cells. These integrated effects contributed to the dramatical reduced expression of TCF1 and ultimately impaired the Tfh cell differentiation.

Highlights

The serine/threonine kinase 3-phosphoinositide-dependent protein kinase 1 (PDK1) is a critical metabolic regulator connecting PI3K and downstream molecules (Park et al, 2009)
To elucidate whether PDK1 regulates T follicular helper (Tfh) cell differentiation, we first evaluated the expression of PDK1 in bifurcation of effector CD4+ T cells into Tfh or Th1 cells upon acute viral infection (Xu et al, 2015)
The expression levels of PD-1, ICOS, and Bcl-6 were much lower in Pdk1fl/fl::Cd4-Cre Tfh cells than those of wild-type littermates (WT) cells (Figure 1E,F)

Summary

Introduction

The serine/threonine kinase 3-phosphoinositide-dependent protein kinase 1 (PDK1) is a critical metabolic regulator connecting PI3K and downstream molecules (Park et al, 2009). PDK1 is crucial for multiple types of immune cell development, such as hematopoietic stem cells, B cells, NK cells, T cells, and cytolytic CD8+ cells (Park et al, 2009; Baracho et al, 2014; Venigalla et al, 2013; Yang et al, 2015; Finlay et al, 2012) Despite these profound effects of PDK1 on the regulation of various immune cell subsets, its role in CD4+ T helper cells, especially T follicular helper (Tfh) cell differentiation, has not been experimentally determined. Except sustained TCR signals, Tfh cells express high levels of many co-receptors for their generation and function, including CD28 and ICOS (Qin et al, 2018). Our data indicated that PDK1 is intrinsically required for Tfh cell formation and effector functions, which is important to understanding the nature of the Tfh cell development

Results

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Materials and methods