CD154 inhibits death of T cells via a Cis interaction with the α5β1 integrin.

Meriem Bachsais,Fawzi Aoudjit,Suzanne Salti,Kossay Zaoui,Ghada S Hassan,Walid Mourad,Lucia R Languino

doi:10.1371/journal.pone.0235753

Meriem Bachsais, Fawzi Aoudjit + Show 5 more

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https://doi.org/10.1371/journal.pone.0235753

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Abstract

CD154 plays a major role in the pathogenesis of several autoimmune and inflammatory diseases. In addition to CD40, soluble CD154 (sCD154) binds to other receptors namely αIIbβ3, αMβ2, α5β1 and αvβ3 integrins. We have previously reported that binding of sCD154 to α5β1 integrin expressed on several human T cell lines is capable of inhibiting Fas-induced cell death. In the current study, we show that such effect of the sCD154/α5β1 interaction is not restricted to the cell death response induced by Fas but could also be exhibited toward other death signals such as TRAIL and TNF- α. We also demonstrate that sCD154 is capable of inhibiting Fas-mediated death of human activated T cells, more importantly of CD4+ than CD8+ T ones. Our data also show that membrane-bound CD154 and α5β1 integrin expressed on the surface of distinct cells failed to influence cell death responses. However, when membrane-bound CD154 and α5β1 are expressed on the surface of same cell, their interaction was capable of down regulating cell death. CD154 was shown to co-localize with the α5β1 integrin on the surface of these cells. These data strongly suggest a cis-type of interaction between CD154 and α5β1 when both are expressed on the same cell surface, rather than a trans-interaction which usually implicates the ligand and its receptor each expressed on the surface of a distinct cell. Taken together, these findings add to the list of roles through which CD154 is contributing to the pathogenesis of autoimmune-inflammatory diseases, i.e. by protecting T cells from death and enhancing their survival.

Highlights

CD154, known as CD40 ligand (CD40L), is an immunomodulator initially described in activated CD4-positive T cells and later found to be expressed on other types of cells such as basophiles, mast cells, activated CD8-positive T cells and platelets [1, 2]
We found that binding of soluble CD154 (sCD154) to α5β1 integrin inhibits apoptosis of T cell lines and human primary T cells induced by the tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and TNF-α
We demonstrated above that membrane-bound CD154 expressed on the surface of CD154-transfected Jurkat E6.1 cells interacting with α5β1 expressed on the same cell surface, inhibited their apoptotic responses while the membrane-bound form of CD154 expressed on another cell interacting with the α5β1 integrin of Jurkat E6.1 cells did not affect the death response of these latter

Summary

Introduction

CD154, known as CD40 ligand (CD40L), is an immunomodulator initially described in activated CD4-positive T cells and later found to be expressed on other types of cells such as basophiles, mast cells, activated CD8-positive T cells and platelets [1, 2]. To other members of the TNF family, in addition to the membrane-bound molecule, CD154 exists in a soluble form (sCD154) that is still biologically active [3] This soluble form is usually released from activated T cells and platelets by proteolytic cleavage [3, 4]. No functional studies were undertaken but authors expected a high biological significance for the CD154/αvβ interaction given the high expression of αvβ on vascular and cancer cells [24]. In this context, we have demonstrated that stimulating an α5β1-positive monocytic cell line with sCD154 induces the activation of MAPK/ERK1/2 pathway and IL-8 production in a CD40-independent manner [23]. Our studies suggest that the antiapoptotic effect of CD154 is exerted in a cis-dependent manner, i.e both CD154 and α5β1 are expressed on the surface of the same cell

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