Galectin-1 Sensitizes Resting Human T Lymphocytes to Fas (CD95)-mediated Cell Death via Mitochondrial Hyperpolarization, Budding, and Fission

Abstract

Galectins have emerged as a novel family of immunoregulatory proteins implicated in T cell homeostasis. Recent studies showed that galectin-1 (Gal-1) plays a key role in tumor-immune escape by killing antitumor effector T cells. Here we found that Gal-1 sensitizes human resting T cells to Fas (CD95)/caspase-8-mediated cell death. Furthermore, this protein triggers an apoptotic program involving an increase of mitochondrial membrane potential and participation of the ceramide pathway. In addition, Gal-1 induces mitochondrial coalescence, budding, and fission accompanied by an increase and/or redistribution of fission-associated molecules h-Fis and DRP-1. Importantly, these changes are detected in both resting and activated human T cells, suggesting that Gal-1-induced cell death might become an excellent model to analyze the morphogenetic changes of mitochondria during the execution of cell death. This is the first association among Gal-1, Fas/Fas ligand-mediated cell death, and the mitochondrial pathway, providing a rational basis for the immunoregulatory properties of Gal-1 in experimental models of chronic inflammation and cancer.

Redundant and Antagonistic Functions of Galectin-1, -3, and -8 in the Elicitation of T Cell Responses

“…In addition, it was shown that, although Gal-1 induces apoptosis of 2-d Con A-activated T cells, it promotes the survival of resting T cells without inducing proliferation (32). In contrast to our observations and those from other investigators, Matarrese et al (33) observed that Gal-1 sensitized human resting T lymphocytes to Fas-mediated cell death and that, at high doses, it was capable of inducing apoptosis in these primary cells. Discrepancies might reflect the different species used (human versus mouse), different protein preparations, or the method used to assess cell death, because phosphati-dylserine exposure is not necessarily associated with Gal-induced apoptosis (34).…”

Novel role for galectin-1 in T-cells under physiological and pathological conditions

“…Even though the signaling pathways responsible for exGal-1 driven T-cell apoptosis have largely been mapped [6,7,[36][37][38], many questions about the exact mechanism by which the cells were sensitized by inGal-1 to exGal-1 mediated apoptosis remain to be elucidated. While the anti-apoptotic effect of intracellular Gal-3 can be explained by the Bcl-2 homolog motif of the protein [39], Gal-1 does not have a homologous segment with any known apoptotic protein, and thus its function in apoptosis must stem from a yet unknown mechanism.…”

Lipid microdomains contribute to apoptosis-associated modifications of mitochondria in T cells

“…37 In particular, overexpression of the human fission protein hFis1, an integral protein of the outer mitochondrial membrane, triggers fission of mitochondria, Cyt c release and subsequent apoptosis. 18,38 Furthermore, Bax colocalizes at mitochondrial fission sites early in the apoptotic process, 39 linking proapoptotic members of the Bcl-2 family to the mitochondrial fission and fusion machinery. Thus, we analyzed the presence and the possible interaction of hFis1 with mitochondrial lipid microdomains.…”

“…17 Among these, h-Fis seems to play a key role. 17,18 This was described as an integral protein of the outer mitochondrial membrane participating to the membrane scission events. Members of the sphingomyelin pathway seem to have a profound influence on the apoptotic cascade, including these mitochondrial changes.…”