4-1BB-dependent inhibition of immunosuppression by activated CD4+CD25+ T cells.
4-1BB (CD137) is a costimulatory molecule involved in the activation and survival of CD4, CD8, and natural killer cells. Although a great deal has been learned as to how 4-1BB-mediated signaling governs the immunity of conventional T cells, the functional role of 4-1BB in the context of CD4(+)CD25(+) regulatory T cell (Tr) activation is largely unknown. Using 4-1BB-intact and -deficient mice, we investigated the effect of the 4-1BB/4-1BB ligand pathway on the suppressive function of Tr cells. Our data indicate that although 4-1BB is expressed on Tr cells, its contribution to their proliferation is minimal. We also showed that signaling through the 4-1BB receptor inhibited the suppressive function of Tr cells in vitro and in vivo. It is interesting that anti-4-1BB-mediated but not anti-GITR-directed inhibition was more potent when Tr cells were preactivated. Collectively, these data indicate that 4-1BB signaling is critical in Tr cell immunity.
Choi
Beom K
BK
Immunomodulation Research Center, University of Ulsan, Korea.
Bae
Jun S
JS
Choi
Eun M
EM
Kang
Woo J
WJ
Sakaguchi
Shimon
S
Vinay
Dass S
DS
Kwon
Byoung S
BS
D053330:4-1BB Ligand; D000818:Animals; D015703:Antigens, CD; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D005260:Female; D006086:Graft vs Host Disease / Q000209:etiology; D007109:Immunity; D008213:Lymphocyte Activation / Q000276:immunology*; D017710:Lymphocyte Transfusion / Q000009:adverse effects; D051379:Mice; D018345:Mice, Knockout; D015375:Receptors, Interleukin-2; D017475:Receptors, Nerve Growth Factor / Q000172:deficiency / Q000276:immunology / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency / Q000276:immunology / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000637:transplantation; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D053330:4-1BB Ligand; D015703:Antigens, CD; D015375:Receptors, Interleukin-2; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C505715:Tnfrsf9 protein, mouse; C505975:Tnfsf9 protein, mouse; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D014409:Tumor Necrosis Factor-alpha