Stimulation with 4-1BB (CD137) inhibits chronic graft-versus-host disease by inducing activation-induced cell death of donor CD4+ T cells

Kim, Juyang; Choi, Woon S.; La, Soojin; Suh, Jae-Hee; Kim, Byoung-sam; Cho, Hong R.; Kwon, Byoung S.; Kwon, Byungsuk

doi:10.1182/blood-2004-06-2080

Cited by 66 publications

(73 citation statements)

References 37 publications

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“…It is possible that in addition to the generation of positive signals through 4-1BB, there might be situations in which 4-1BB can transmit negative signals to a CD8 cell. This possibility would go along with the suggestion from autoimmune and graft-vs-host disease studies, in which anti-4-1BB is suppressive, that chronic 4-1BB signals may lead to apoptosis (activation-induced cell death) of pathogenic T cells (34,61). This idea is feasible because we observed stable 4-1BB expression throughout the course of the primary adenovirus response.…”

Section: Discussionmentioning

confidence: 80%

“…One of the reasons might be the promiscuous expression of 4-1BB on many kinds of immune cells that have specific and perhaps opposing roles in various pathophysiological circumstances. For example, it has been suggested that negative effects of anti-4-1BB could be due to promoting apoptosis of CD4 cells (34,61), and that CD4 and CD8 cells respond differently to 4-1BB ligation (58). Alternatively, anti-4-1BB has been proposed to induce regulatory cells, either in the CD8 lineage (31,62), or in the dendritic cell lineage (30).…”

Section: Discussionmentioning

confidence: 99%

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Functional Dichotomy between OX40 and 4-1BB in Modulating Effector CD8 T Cell Responses

Lee

Park

Song

et al. 2006

The Journal of Immunology

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Members of the TNFR family are thought to deliver costimulatory signals to T cells and modulate their function and survival. In this study, we compare the role of two closely related TNFR family molecules, OX40 and 4-1BB, in generating effector CD8 T cells to Ag delivered by adenovirus. OX40 and 4-1BB were both induced on responding naive CD8 T cells, but 4-1BB exhibited faster and more sustained kinetics than OX40. OX40-deficient CD8 T cells initially expanded normally; however, their accumulation and survival at late times in the primary response was significantly impaired. In contrast, 4-1BB-deficient CD8 T cells displayed hyperresponsiveness, expanding more than wild-type cells. The 4-1BB-deficient CD8 T cells also showed enhanced maturation attributes, whereas OX40-deficient CD8 T cells had multiple defects in the expression of effector cell surface markers, the synthesis of cytokines, and in cytotoxic activity. These results suggest that, in contrast to current ideas, OX40 and 4-1BB can have a clear functional dichotomy in modulating effector CD8 T cell responses. OX40 can positively regulate effector function and late accumulation/survival, whereas 4-1BB can initially operate in a negative manner to limit primary CD8 responses.

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Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Functional Dichotomy between OX40 and 4-1BB in Modulating Effector CD8 T Cell Responses

Lee

Park

Song

et al. 2006

The Journal of Immunology

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“…We induced cGVHD by transferring total or Treg cell-depleted DBA/2 spleen/lymph node cells into unirradiated BDF1 mice. Three weeks after disease induction, we measured levels of anti-DNA IgG1 autoantibody, a predominant immunoglobulin isotype in cGVHD (Kim et al, 2005;2006b). Introduction of Treg cell-depleted parental cells induced significantly lower levels of anti-DNA IgG1 in the recipient than did introduction of total parental cells (Figure 1).…”

Section: Resultsmentioning

confidence: 99%

Maintenance of CD8+T-cell anergy by CD4+CD25+ regulatory T cells in chronic graft-versus-host disease

Kim

Kim²,

Choi³

et al. 2006

Exp Mol Med

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In a murine model of systemic lupus erythematosus (SLE)-like chronic graft-versus-host disease (cGVHD), donor CD8 + T cells rapidly fall into anergy to host cells, while donor CD4 + T cells hyperactivate B cells and break B-cell tolerance to self-Ags in the recipient mouse. The functional recovery of donor CD8 + T cells can result in the conversion of cGVHD to acute GVHD (aGVHD), indicating that donor CD8 + T-cell anergy is a restriction factor in the development of cGVHD. In this report, we present evidence that donor CD4 + CD25 + regulatory T cells (T reg cells) are critical in maintaining the donor CD8 + T-cell anergy and thus suppressing the development of aGVHD in mice that are naturally prone to cGVHD. Our results provide a novel insight into the role of T reg cells in determining cGVHD versus aGVHD.

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“…There exists several circumstantial evidence sup- porting a higher Ab response in 4-1BB-deficient mice; 4-1BB-deficient mice have increased basal levels of Ig (Vinay et al, 2003). Moreover, blockage of interactions between 4-1BB and 4-1BBL elevates levels of autoantibody in cGVHD (Nozawa et al, 2001), whereas stimulation of 4-1BB abrogates T cell-dependent Ab response (Mittler et al, 1999;Sun et al, 2002;Foell et al, 2003;Wu et al, 2003;Foell et al, 2004;Seo et al, 2004;Kim et al, 2005) and sustained stimulation of 4-1BB in 4-1BBL transgenic mice induces progressive depletion of B cells and subsequent abrogation of Ab production (Zhu et al, 2000). It seems that 4-1BB signals are involved in Th1 immune responses (our unpublished data) and it has been shown that Th1-specific Ab responses are impaired in 4-1BB-deficient mice (Kwon et al, 2002b).…”

Section: Discussionmentioning

confidence: 99%

“…It seems that, even though anti-4-1BBL mAb could not block proliferation of T cells initially, it was effective in decreasing the number of alloreactive T cells at the later stage of alloimmune responses (Cho et al, 2004). In the chronic graft-versus-host disease (cGVHD) setting, stimulation of 4-1BB was highly effective in preventing and curing cGVHD by inducing AICD of pathogenic donor CD4 + T cells (Kim et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

4-1BB (CD137) signals depend upon CD28 signals in alloimmune responses

Eun-A

Kim²,

Seo³

et al. 2006

Exp Mol Med

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Our previous study has demonstrated that there is a significant delay of Balb/c cardiac allograft rejection in the C57BL/6 4-1BB-deficient knockout recipient. In this study, we examined the effect of combined blockade of the 4-1BB and CD28 costimulatory pathways on cardiac allograft rejection in the C57BL/6 → Balb/c model. A long-term cardiac allograft survival was induced in CD28/4-1BB-deficient mice (＞ 100 days survival in 3 of 4 mice), which was comparable with CD28-deficient mice (＞ 100 days survival in 2 of 5 mice; P ＜ 0.2026). There was no long-term cardiac allograft survival in either wild-type (WT) or 4-1BB-deficient mice, even though 4-1BB-deficient recipients showed a significant delay of cardiac allograft rejection than WT mice. An in vitro mixed leukocyte reaction (MLR) assay showed that 4-1BB-deficient and WT mouse T cells had a similar responsiveness to allostimulation, whereas CD28-and CD28/4-1BB-deficient mouse T cells had a defective responsiveness to allostimulation. Furthermore, 4-1BB-deficient mice showed a similar CTL but an elevated Ab response against alloantigens as compared to WT mice, and the alloimmune responses of 4-1BB-deficient mice were abrogated in the CD28-deficient background. Overall, these results indicate that the CD28 costimulatory pathway plays a major role in the alloimmune response and that 4-1BB signals are dependent upon CD28 signals.

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Stimulation with 4-1BB (CD137) inhibits chronic graft-versus-host disease by inducing activation-induced cell death of donor CD4+ T cells

Cited by 66 publications

References 37 publications

Functional Dichotomy between OX40 and 4-1BB in Modulating Effector CD8 T Cell Responses

Functional Dichotomy between OX40 and 4-1BB in Modulating Effector CD8 T Cell Responses

Maintenance of CD8+T-cell anergy by CD4+CD25+ regulatory T cells in chronic graft-versus-host disease

4-1BB (CD137) signals depend upon CD28 signals in alloimmune responses

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