The Interaction of CD154 with the α5β1 Integrin Inhibits Fas-Induced T Cell Death.

Meriem Bachsais,Nada Alaaeddine,Walid Mourad,Daniel Yacoub,Nadim Naddaf,Ghada S Hassan,Suzanne Salti,Fawzi Aoudjit,Lucia R Languino

doi:10.1371/journal.pone.0158987

Abstract

CD154, a critical regulator of the immune response, is usually associated with chronic inflammatory, autoimmune diseases as well as malignant disorders. In addition to its classical receptor CD40, CD154 is capable of binding other receptors, members of the integrin family, the αIIbβ3, αMβ2 and α5β1. Given the role attributed to integrins and particularly the β1 integrins in inhibiting apoptotic events in normal as well as malignant T cells, we were highly interested in investigating the role of the CD154/α5β1 interaction in promoting survival of malignant T cells contributing as such to tumor development and/or propagation. To support our hypothesis, we first show that soluble CD154 binds to the T-cell acute lymphoblastic leukemia cell line, Jurkat E6.1 in a α5β1-dependent manner. Binding of soluble CD154 to α5β1 integrin of Jurkat cells leads to the activation of key survival proteins, including the p38 and ERK1/2 mitogen-activated protein kinases (MAPKs), phosphoinositide 3 kinase (PI-3K), and Akt. Interestingly, soluble CD154 significantly inhibits Fas-mediated apoptosis in T cell leukemia-lymphoma cell lines, Jurkat E6.1 and HUT78 cells, an important hallmark of T cell survival during malignancy progression. These anti-apoptotic effects were mainly mediated by the activation of the PI-3K/Akt pathway but also involved the p38 and the ERK1/2 MAPKs cascades. Our data also demonstrated that the CD154-triggered inhibition of the Fas-mediated cell death response was dependent on a suppression of caspase-8 cleavage, but independent of de novo protein synthesis or alterations in Fas expression on cell surface. Together, our results highlight the impact of the CD154/α5β1 interaction in T cell function/survival and identify novel targets for the treatment of malignant disorders, particularly of T cell origin.

Highlights

CD154, known as CD40 ligand or gp-39, is a 33 kDa type II transmembrane protein that belongs to the tumor necrosis factor (TNF) superfamily
Co-incubation of soluble CD154 (sCD154)-Alexa with soluble CD40 had no effect on sCD154 binding to Jurkat E6.1 cells, while it entirely reversed its binding to BJAB cells
In search of the physiological outcome of the CD154/α5β1 interaction in the function of malignant T cells, and based on earlier observations showing that binding of collagen, an extracellular matrix protein, to some members of the β1 integrin inhibits Fasinduced cell death [27], we evaluated the impact of sCD154 on Fas-induced apoptosis in T cell acute lymphoblastic leukemia (T-ALL) cell lines

Summary

Introduction

CD154, known as CD40 ligand or gp-39, is a 33 kDa type II transmembrane protein that belongs to the tumor necrosis factor (TNF) superfamily. The interaction of CD154 with its classical receptor on B cells, CD40, a member of the TNF receptor (TNFR) family, is of critical importance for immunoglobulin isotype switching during humoral immune response [3]. This axis plays a predominant role in cell-mediated immunity, through the up-regulation of adhesion and costimulatory molecules, and the production of pro-inflammatory cytokines, chemokines, growth factors, matrix metalloproteinases and procoagulants [4,5,6,7]. Circulating levels of soluble CD154 (sCD154), which originate from the proteolytic cleavage of membrane-bound CD154 at the surface of activated T cells and platelets, have emerged as strong indicators of immune activity in inflammatory diseases [13,14,15,16] and of prognosis level in some types of cancers [17,18,19]

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