A Critical Role of CD30 Ligand/CD30 in Controlling Inflammatory Bowel Diseases in Mice

et al. 2010

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A CD30 ligand (CD30L; CD153) and its receptor, CD30, is a membrane-associated glycoprotein belonging to the TNF superfamily and TNFR superfamily. These were expressed preferentially by activated CD4+T cells. In this paper, we show that CD44lowCD62hiCD4+ T cells from CD30L−/− or CD30−/− mice exhibited impaired differentiation into Th17 cells but an increased ability to produce IL-2 after in vitro culture under Th17-polarizing conditions. Neutralization with IL-2 by anti–IL-2 mAb partly restored the ability of Th17 differentiation in CD30L−/− or CD30−/− T cells. Stimulation via CD30L by immobilized anti-CD30L mAb suppressed IL-2 production by CD30−/−CD4+ T cells, indicating that the reverse signal to CD30L is responsible for downregulation of IL-2 production. In vivo Th17 differentiation of CD30L−/−CD4+CD45RBhigh T cells was also impaired after transfer into SCID mice, whereas CD30L+/+CD4+CD45RBhigh T cells normally differentiated into Th17 cells in CD30L−/−SCID mice. The results of these studies demonstrate that CD30L/CD30 signaling executed by the T-T cell interaction plays a critical role in Th17 cell differentiation, at least partly via downregulation of IL-2 production.

Section: /2supporting

confidence: 60%

mentioning

confidence: 99%

CD30 Ligand/CD30 Plays a Critical Role in Th17 Differentiation in Mice

Sun

Yamada²,

et al. 2010

Self Cite

“…We previously reported that CD30L 2/2 mice were susceptible to Th2-type, experimental OXA-induced colitis but resistant to Th1-type, TNBS-induced acute colitis. The level of Th1-type cytokine IFN-g in T-LPLs was significantly lower in OXA-or TNBS-treated CD30L 2/2 mice than that in WT mice (29). We also found that CD30L 2/2 mice were susceptible to infection with bacillus Calmette-Guérin in association with reduced Th1 responses (36).…”

Section: Discussionsupporting

confidence: 50%

“…We previously reported that CD30L 2/2 mice were susceptible to Th2-type OXA-induced colitis but resistant to Th1-type TNBS-induced acute colitis (29). Furthermore we have recently found that colitis was attenuated in SCID mice to which CD30L 2/2 CD4 + CD45RB high T cells have been transferred, suggesting that CD30L is involved in the pathogenesis of Th1-type colitis (12).…”

mentioning

confidence: 97%

CD30 Ligand Is a Target for a Novel Biological Therapy against Colitis Associated with Th17 Responses

Sun

Yamada²,

et al. 2010

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We have previously found that CD30 ligand (CD30L; CD153)/CD30 signaling executed by the T–T cell interaction plays a critical role in Th17 cell differentiation, at least partly via downregulation of IL-2 production. In this study, we investigated the role of CD30L in the development of colitis experimentally induced by dextran sulfate sodium (DSS), in which IL-17A is involved in the pathogenesis. CD30L−/− mice were resistant to both acute colitis induced by administration of 3 to ∼5% DSS and to chronic colitis induced by administration of 1.5% DSS on days 0–5, 10–15, and 20–25 as assessed by weight loss, survival rate, and histopathology. The levels of IFN-γ, IL-17A, and IL-10 were significantly lower but the IL-2 level higher in the lamina propria T lymphocytes of CD30L−/− mice than those in lamina propria T lymphocytes of wild-type mice after DSS administration. Soluble murine CD30-Ig fusion protein, which was capable of inhibiting Th17 cell differentiation in vitro, ameliorated both types of DSS-induced colitis in wild-type mice. Modulation of CD30L/CD30 signaling by soluble CD30 could be a novel biological therapy for inflammatory diseases associated with Th17 responses.

“…We have recently reported that CD30L Ϫ/Ϫ mice were susceptible to Th2 type experimentally oxazoloneinduced colitis, but resistant to Th1 type trinitrobenzenesulfonic acid-induced acute colitis. The levels of Th2 type cytokines such as IL-4 and IL-13 in the lamina propria T cells were significantly higher, but the levels of IFN-␥ were lower in oxazolone-or trinitrobenzenesulfonic acid-treated CD30L Ϫ/Ϫ mice than in WT mice (35). In this study, we found that CD30L Ϫ/Ϫ mice were also susceptible to i.t.…”

Section: Discussionmentioning

confidence: 45%

A Novel Role of CD30L/CD30 Signaling by T-T Cell Interaction in Th1 Response against Mycobacterial Infection

Tang¹,

Yamada²,

et al. 2008

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A CD30 ligand (CD30L, CD153) is a type II membrane-associated glycoprotein belonging to the TNF family. To illustrate the potential role of CD30L in CD4+ Th1 cell responses, we investigated the fate of Ag-specific CD4+ T cells in CD30L-deficient (CD30L−/−) mice after Mycobacterium bovis bacillus Calmette-Guérin (BCG) infection. The number of bacteria was significantly higher in organs of CD30L−/− mice than in wild-type (WT) mice 4 wk postinfection. The numbers of purified protein derivative- or Ag85B-specific-IFN-γ-producing-CD4+ T cells in spleen, lung, or peritoneal exudate cells were significantly fewer in CD30L−/− mice than in WT mice. During the infection, CD30L was expressed mainly by CD44+CD3+CD4+ T cells but not by CD3+CD8+ T cells, B cells, dendritic cells, or macrophages. Costimulation with agonistic anti-CD30 mAb or coculturing with CD30L-transfected P815 cells restored IFN-γ production by CD4+ T cells from BCG-infected CD30L−/− mice. Coculturing with CD30L+/+CD4+ T cells from BCG-infected WT mice also restored the number of IFN-γ+CD30L−/−CD4+ T cells. When transferred into the CD30L+/+ mice, Ag-specific donor CD30L−/− CD4+ T cells capable of producing IFN-γ were restored to the compared level seen in CD30L+/+ CD4+ T cells on day 10 after BCG infection. When naive CD30L+/+ T cells were transferred into CD30L−/− mice, IFN-γ-producing-CD4+ Th1 cells of donor origin were normally generated following BCG infection, and IFN-γ-producing-CD30L−/−CD4+ Th1 cells of host origin were partly restored. These results suggest that CD30L/CD30 signaling executed by CD30+ T-CD30L+ T cell interaction partly play a critical role in augmentation of Th1 response capable of producing IFN-γ against BCG infection.