Involvement of the intrinsic and extrinsic cell‐death pathways in the induction of apoptosis of mature lymphocytes by the Escherichia coli heat‐labile enterotoxin

Abstract

Escherichia coli heat-labile enterotoxin (LT) exhibits a broad range of immunomodulatory activities, including the induction of lymphocyte-programmed cell death. In previous studies, we have demonstrated that in vivo LT promotes apoptosis of immature T and B cells through the stimulation of endogenous glucocorticoids. In the present study, we show that the extrinsic cell-death pathway as well as the apoptosis-inducing factor do not participate in the LT-induced elimination of thymocytes. In contrast to developing lymphocytes, LT promotes the death of mature lymphocytes by both glucocorticoid-and Fas death receptor/Fas ligand-dependent mechanisms. However, the dependency of these mechanisms in the LT-induced cell-death activity seems to be different among CD4 + and CD8 + T cells. Altogether, our study shows that the same bacterial toxin can induce apoptosis of lymphoid cells through several mechanisms depending on the status of differentiation of these cells.

GITR contributes to the systemic adjuvanticity of the Escherichia coli heat‐labile enterotoxin

“…As LT promotes an intense T-cell apoptosis [3,16], we explored whether the maintenance in the number of CD4…”

“…For that we explored first the effects of LT in BALB/c mice after bilateral adrenalectomy, which severely impairs LT-induced lymphocyte apoptosis [3,16]. In these adrenalectomized mice, f.p.…”

“…Both toxins induce the maturation of DC, increasing their antigen presentation capability, their migration to the lymph nodes and their interaction with naive T cells [14]. In addition, CT and LT may act directly on lymphocytes inducing their activation and/or cell death [3,15,16]. We have previously shown that administration of LT promotes an intense but incomplete apoptosis of lymphocytes [5,16].…”

“…In addition, CT and LT may act directly on lymphocytes inducing their activation and/or cell death [3,15,16]. We have previously shown that administration of LT promotes an intense but incomplete apoptosis of lymphocytes [5,16]. This, together with the capacity of the toxin to stimulate the remaining lymphocytes [15], may explain the apparent paradox that an agent with such a potent pro-apoptotic activity can be an adjuvant.…”

“…An interesting observation is that the LT-mediated cell death is only observed after its systemic administration [3], suggesting that the immunomodulatory properties of LT are highly influenced by the route of toxin delivery. Because of the glucocorticoid-mediated effect of LT on apoptosis [3,16], our interest was focused on the glucocorticoid-induced TNFR-related protein (GITR), a member of the TNFR superfamily that is constitutively expressed at high levels in Treg and at low levels on conventional CD4…”