Lhuillier Claire, Barjon Clément, Niki Toshiro, Gelin Aurore, Praz Françoise, Morales Olivier, Souquere Sylvie, Hirashima Mitsuomi, Wei Ming, Dellis Olivier, Busson Pierre
From the Université Paris-Sud, 15 Rue Georges Clémenceau, 91400, Orsay, France, the CNRS, UMR 8126, Institut Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif Cedex, France, the Cellvax, Ecole Nationale Vétérinaire d'Alfort, 7 Avenue du Général de Gaulle, 94704 Maisons-Alfort Cedex, France.
the Department of Immunology and Immunopathology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan, the GalPharma Co., Ltd., Takamatsu, Kagawa 761-0301, Japan.
J Biol Chem. 2015 Jul 3;290(27):16797-811. doi: 10.1074/jbc.M115.661272. Epub 2015 May 6.
Galectin-9 (gal-9) is a multifunctional β-galactoside-binding lectin, frequently released in the extracellular medium, where it acts as a pleiotropic immune modulator. Despite its overall immunosuppressive effects, a recent study has reported bimodal action of gal-9 on human resting blood T cells with apoptosis occurring in the majority of them, followed by a wave of activation and expansion of Th1 cells in the surviving population. Our knowledge of the signaling events triggered by exogenous gal-9 in T cells remains limited. One of these events is cytosolic calcium (Ca(2+)) release reported in some murine and human T cells. The aim of this study was to investigate the contribution of Ca(2+) mobilization to apoptotic and nonapoptotic effects of exogenous gal-9 in human T cells. We found that the T cell receptor (TCR)-CD3 complex and the Lck kinase were required for Ca(2+) mobilization but not for apoptosis induction in Jurkat cells. These data were confirmed in human CD4(+) T cells from peripheral blood as follows: a specific Lck chemical inhibitor abrogated Ca(2+) mobilization but not apoptosis induction. Moreover, Lck activity was also required for the production of Th1-type cytokines, i.e. interleukin-2 and interferon-γ, which resulted from gal-9 stimulation in peripheral CD4(+) T cells. These findings indicate that gal-9 acts on T cells by two distinct pathways as follows: one mimicking antigen-specific activation of the TCR with a mandatory contribution of proximal elements of the TCR complex, especially Lck, and another resulting in apoptosis that is independent of this complex.
半乳糖凝集素-9（gal-9）是一种多功能的β-半乳糖苷结合凝集素，经常释放到细胞外介质中，在那里它作为一种多效性免疫调节剂发挥作用。尽管其具有总体免疫抑制作用，但最近的一项研究报告称，gal-9对人静息血液T细胞具有双峰作用，其中大多数细胞发生凋亡，随后存活群体中的Th1细胞出现一波激活和扩增。我们对外源性gal-9在T细胞中引发的信号事件的了解仍然有限。这些事件之一是在一些小鼠和人类T细胞中报道的胞质钙（Ca(2+)）释放。本研究的目的是探讨Ca(2+)动员对外源性gal-9在人T细胞中的凋亡和非凋亡作用的贡献。我们发现，T细胞受体（TCR）-CD3复合物和Lck激酶是Jurkat细胞中Ca(2+)动员所必需的，但不是诱导凋亡所必需的。这些数据在外周血人CD4(+) T细胞中得到如下证实：一种特异性Lck化学抑制剂消除了Ca(2+)动员，但没有消除凋亡诱导。此外，外周CD4(+) T细胞中gal-9刺激产生的Th1型细胞因子，即白细胞介素-（此处原文可能有误，推测为白细胞介素-2）和干扰素-γ，其产生也需要Lck活性。这些发现表明，gal-9通过两种不同的途径作用于T细胞：一种途径模仿TCR的抗原特异性激活，TCR复合物的近端元件，特别是Lck起强制性作用；另一种途径导致与该复合物无关的凋亡。
