Abstract
4-1BB (CD137, TNFRSF9), a member of the activation-induced tumor necrosis factor receptor family, is a powerful T-cell costimulatory molecule. It generally enhances CD8+ T responses and even breaks the tolerance of CD8+ T cells in an antigen-specific manner. In the present study we found that it was expressed in the placentas of pregnant mice and that its expression coincided with that of the immunesuppressive enzyme indoleamine 2,3-dioxygenase (IDO). Therefore, we investigated whether 4-1BB signaling is involved in fetal rejection using agonistic anti-4-1BB mAb and 4-1BB-deficient mice. Treatment with agonistic anti-4-1BB mAb markedly increased the rate of rejection of allogeneic but not syngeneic fetuses, and this was primarily dependent on CD8+ T cells. Complement component 3 (C3) seemed to be the effector molecule because 4-1BB triggering resulting in accumulation of C3 in the placenta, and this accumulation was also reversed by anti-CD8 mAb treatment. These findings demonstrate that 4-1BB triggering breaks the tolerance of CD8+ T cells to alloantigens in the placenta. Moreover, triggering 4-1BB protected the pregnant mice from Listeria monocytogenes (LM) infection, but led to rejection of semi-allogeneic fetuses. Therefore, given the cross-recognition of alloantigen by pathogen-reactive CD8+ T cells, the true function of 4-1BB may be to reverse the hypo-responsiveness of pathogen-reactive CD8+ T cells in the placenta in cases of infection, even if that risks losing the fetus.
Highlights
Since interactions between the maternal immune system and fetal tissues that express paternally inherited alloantigens should provoke immune responses against fetal tissues, successful pregnancy depends on mechanisms that suppress maternal immune activation by fetal alloantigens [1]
It has been reported that diverse members of the tumor necrosis factor (TNF) superfamily are expressed in placental tissue [12] and 4-1BB is expressed in the pregnant mouse uterus [13]
component 3 (C3) deposition was not detectable in any of the mice carrying syngeneic fetuses (Figure 3A, 3C, 3E, and 3G). These results indicate that maternal CD8+ T cells play crucial roles in the 4-1BB-mediated rejection of allogeneic fetuses
Summary
Since interactions between the maternal immune system and fetal tissues that express paternally inherited alloantigens should provoke immune responses against fetal tissues, successful pregnancy depends on mechanisms that suppress maternal immune activation by fetal alloantigens [1]. 4-1BB (CD137, TNFRSF9), a member of the tumor necrosis factor (TNF) receptor superfamily, functions as an inducible costimulatory molecule for T cells [4], [5], [6]. 4-1BB signaling has dual roles in modulating immune responses [7], 41BB triggering in vivo generally enhances immune responses against tumors or viruses by preferentially stimulating CD8+ T responses [4], [8]. We examined the possible roles of 4-1BB signaling in the placenta using agonistic anti-4-1BB mAb, blocking anti-4-1BB ligand mAb, and 4-1BB-deficient mice, and found that 4-1BB triggering resulted in rejection of semi-allogeneic fetuses, but was required to protect the pregnant mice from infections
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