title: 4-1BB signaling breaks the tolerance of maternal CD8+ T cells that are reactive with alloantigens.
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.
authors.affiliation: Division of Cancer Biology, National Cancer Center, Goyang, Kyeonggi-do, Korea.
authors.forename: Kwang H
authors.initials: KH
authors.lastname: Kim
authors.forename: Beom K
authors.initials: BK
authors.lastname: Choi
authors.forename: Jung D
authors.initials: JD
authors.lastname: Kim
authors.forename: Young H
authors.initials: YH
authors.lastname: Kim
authors.forename: Sun K
authors.initials: SK
authors.lastname: Lee
authors.forename: Jae H
authors.initials: JH
authors.lastname: Suh
authors.forename: Sang C
authors.initials: SC
authors.lastname: Lee
authors.forename: Sang W
authors.initials: SW
authors.lastname: Kang
authors.forename: Byoung S
authors.initials: BS
authors.lastname: Kwon
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D005260:Female; D005333:Fetus / Q000276:immunology; D007108:Immune Tolerance; D007519:Isoantigens / Q000276:immunology*; D008089:Listeria monocytogenes / Q000276:immunology; D008088:Listeriosis / Q000276:immunology / Q000517:prevention & control; D008297:Male; D051379:Mice; D010920:Placenta / Q000276:immunology / Q000378:metabolism; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000276:immunology / Q000517:prevention & control; D015398:Signal Transduction; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000276:immunology* / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D007519:Isoantigens; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9