Prostaglandin E2 enhances T-cell proliferation by inducing the costimulatory molecules OX40L, CD70, and 4-1BBL on dendritic cells

Abstract

Dendritic cell (DC)-based immunotherapy of malignant diseases relies on 2 critical parameters: antigen transport from the periphery to draining lymph nodes and efficient priming of primary and stimulation of secondary immune responses. Prostaglandin E 2 (PGE 2 ) signaling has been shown to be pivotal for DC migration toward lymph node-derived chemokines in vitro and in vivo. Here, we demonstrate that PGE 2 induced the expression of the costimulatory molecules OX40L, CD70, and 4-1BBL on human DCs. Short triggering by PGE 2 early during DC maturation was sufficient to induce the costimulatory molecules. The expression of the costimulatory molecules was independent of the maturation stimulus but strictly dependent on PGE 2 on both monocytederived (Mo) DCs and peripheral blood myeloid (PB) DCs. PGE 2 -matured MoDCs showed enhanced costimulatory capacities resulting in augmented antigenspecific CD4 ؉ and CD8 ؉ T-cell prolifera- IntroductionDendritic cells (DCs) are key players in the defense against pathogens because of their unique capacity to induce primary and secondary T-cell responses. By presenting specific antigens on major histocompatibility complex and by expressing costimulatory molecules, DCs provide essential signals for optimal T-cell activation, prevention of tolerance, and development of T-cell immunity. The most important costimulatory receptor for early proliferation of naive T cells is CD28, which interacts with CD80 or CD86 on DCs. 1 However, CD28-CD80/86 costimulatory interactions cannot fully account for an efficient long-lasting T-cell response or the generation of memory T cells. 2 T-cell proliferation and survival at later phases and the development of memory T cells depend on additional costimulatory molecules belonging to the tumor necrosis factor (TNF)/TNF receptor (TNFR) superfamily and include OX40L/OX40, 4-1BBL/4-1BB, and CD70/CD27. 3 OX40 is induced on activated T cells and provides an essential signal for optimal CD4 ϩ T-cell function 4-7 as well as for the generation of memory T cells [8][9][10] by prolonging the survival of effector T cells. 9 Signaling through OX40 is controlled in vivo by the availability of its ligand OX40L. The expression of OX40L is tightly regulated and can be induced on antigen-presenting cells (APCs), such as DCs 11,12 and B cells 13 and microglia. 14 The lack of OX40L on APCs results in a marked reduction of cytokine production and proliferation of T-helper cells. 5,7 Murine DCs transfected with mRNA encoding OX40L induce enhanced antitumor activity in vivo, whereas transfection of OX40L mRNA in human monocyte-derived (Mo) DCs improves the induction of antigen-specific cytotoxic T lymphocytes (CTLs) in vitro. 15 CD27 is expressed on naive CD4 ϩ and CD8 ϩ T cells 16 and on primed B cells, 17 and triggering of CD27 by CD70 supports T-cell survival. Consequently, constant activation of CD27 by persistent transgenic expression of CD70 on mouse B cells leads to excessive T-cell proliferation. 18,19 CD70 expression is transiently induced on T cells, B cells, a...

Ambivalent effects of dendritic cells displaying prostaglandin E2‐induced indoleamine 2,3‐dioxygenase

“…1A). Consistent with previous findings, DCs exposed to cytokines with PGE 2 up-regulated CCR7, a key factor for supporting the DC migratory capacity [28] and the costimulatory molecule OX40L [29] (Fig. 1A).…”

“…As a molecular correlate, PGE 2 was reported to mediate up-regulation of a) T cells were cultured and stimulated as described in Figure 5. co-stimulatory molecules, for example OX40L and CD70 [29]. Similarly, our data show that exposing iDCs to the cytokine cocktail with PGE 2 resulted in a mature DC phenotype by up-regulation of co-stimulatory DC molecules, including OX40L.…”

“…The role of PGE 2 in directing DCs to exert an immune stimulatory or immune regulatory effect on T-cell responses, particularly with respect to PGE 2 -induced IDO induction in human DCs, has recently been controversially discussed. In prior studies, PGE 2 was shown to cooperate with TNF-α to support the development of a mature, highly immunostimulatory DC phenotype [19,20] co-stimulatory molecules, for example OX40L and CD70 [29]. Similarly, our data show that exposing iDCs to the cytokine cocktail with PGE 2 resulted in a mature DC phenotype by up-regulation of co-stimulatory DC molecules, including OX40L.…”

Dendritic cells in cancer immunotherapy

“…In our 62-patient trial (our unpublished data), in metastatic melanoma, tumor-peptide-specific ex vivo detectable (Elispot, tetramer staining) IFN-g-producing CD4 1 T cells were regularly detectable. This is surprising given the low amounts of IL-12p70 released from cocktailmatured DC in vitro but may be explained by their expression of CD70 [20,54]. The vaccine-specific Th cells were FOXP3-negative, indicating that vaccine-specific natural Treg were not induced, which is counterintuitive to a previous report [55], yet compatible with recent Treg cloning data [56].…”

Impact of cyclooxygenase-2 and prostaglandin-E2 expression on clinical outcome after pulmonary metastasectomy

“…Dependent on the binding to different prostanoid receptor types PGE-2 can act as both pro-and anti-inflammatory. As a pro-inflammatory mediator it regulates the expression profile of dendritic cells and enhances T cell activation (33). This is especially important in CRC, a tumor type considered highly immunogenic.…”