Murine B7-H3 Is a Negative Regulator of T Cells

Prasad, Durbaka V. R.; Nguyen, Thi Thuy Hang; Li, Zhaoxia; Yang, Yang; Duong, Julie; Wang, Ying; Dong, Chen

doi:10.4049/jimmunol.173.4.2500

Cited by 299 publications

(281 citation statements)

References 44 publications

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“…Lastly, while our data demonstrating a positive regulatory pathway for B7-H3 are consistent with other work [9,12,14], they differ from reports showing negative regulatory functions of mB7-H3 [15,16]. The reasons for this are unclear, though certainly different targeting strategies, assays, and models were employed.…”

Section: Discussionsupporting

confidence: 83%

“…However, recently Suh et al [15] published the first characterization of a B7-H3 -/-mouse whose use for in vitro and in vivo studies suggested, surprisingly, that B7-H3 has a suppressive effect on mouse T cell activation and functions, leading the authors to suggest that B7-H3 is involved in feedback inhibition of Th1-mediated immune responses. Similarly, employing an anti-B7-H3 mAb, Prasad et al [16] showed a negative regulatory effect of B7-H3 on T cells. Hence, the overall effects of B7-H3 on immune functions are controversial as a result of contrasting data from various models.…”

Section: Introductionmentioning

confidence: 96%

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B7‐H3 promotes acute and chronic allograft rejection

et al. 2005

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The B7 homolog B7-H3 is important for the regulation of immune responses though its functions in vivo are controversial. We report the first clinical and experimental data concerning expression and function of B7-H3 in alloresponses. Immunohistological and molecular analyses showed B7-H3 expression by cells mediating rejection of human and mouse allografts. To analyze the significance of B7-H3 in rejecting allografts, we generated B7-H3 -/-mice and showed that targeting of B7-H3 was synergistic with other forms of immune modulation; e.g. a regimen of rapamycin gave 12-14 days of survival in wild-type controls but led to permanent cardiac and islet allograft survival in B7-H3 -/-mice. Cardiac allografts in treated B7-H3 -/-mice showed markedly decreased production of key cytokine, chemokine and chemokine receptor mRNA transcripts as compared to wild-type controls. The incidence of chronic rejection in two different cardiac allograft models was also inhibited in B7-H3 -/-as compared to wild-type recipients. Lastly, in addition to the expected antigen-presenting cell expression of B7-H3, CD4 and CD8 T cells showed B7-H3 induction upon cell activation, and both dendritic cell-and T cell-expressed B7-H3 each enhanced T cell proliferation in vitro and in vivo. We conclude that B7-H3 promotes T cell-mediated immune responses and the development of acute and chronic allograft rejection.

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Section: Discussionsupporting

confidence: 83%

Section: Introductionmentioning

confidence: 96%

B7‐H3 promotes acute and chronic allograft rejection

et al. 2005

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“…B7-H3 knockout mice showed increased airway hypersensitivity and earlier onset of experimental autoimmune encephalomyelitis (20). Similar results were obtained using B7-H3 blocking Abs, notably that T cells increased cytokine production and experimental autoimmune encephalomyelitis symptoms were exacerbated by B7-H3 blockade (19). In contrast to reports in humans, tumor expression of B7-H3 enhances cytotoxicity (21,22).…”

Section: B7-h3 Is Inhibitory or Costimulatorycontrasting

confidence: 54%

“…Similar to the other B7 family members, subsequent studies have shown that B7-H3 can mediate inhibitory effects (17,19,20) on T cell function as well as costimulatory effects (15,(21)(22)(23). Unlike B7-1 and B7-2, B7-H3 has been shown to also be expressed on nonhemopoietic cells (17).…”

Section: Interactions Of T Cells With Fibroblast-like Synoviocytesmentioning

confidence: 99%

Interactions of T Cells with Fibroblast-Like Synoviocytes: Role of the B7 Family Costimulatory Ligand B7-H3

Tran

Thacker

Louie

et al. 2008

The Journal of Immunology

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Fibroblast-like synoviocytes (FLS) and T cells can activate each other in vitro, and in vivo interactions between these cells may be important in rheumatoid arthritis (RA), yet FLS lack significant expression of CD28 ligands. We sought to identify molecules homologous to CD28 ligands that are strongly expressed by FLS, and documented strong B7-H3 expression on FLS and by fibroblasts of other tissues, which was unaffected by a variety of cytokines. Western blot analysis of FLS lysates showed predominant expression of the larger, four Ig-like domain isoform of B7-H3. Immunohistological sections of RA synovial tissue showed strong staining for B7-H3 on FLS. Cells expressing B7-H3 were distinct from but in close proximity to cells that expressed CD45, CD20, and CD3. Confocal microscopy of FLS and T cell cocultures showed localization of B7-H3 in the region of the T cell-FLS contact point, but distinct from the localization of T cell CD11a/CD18 (LFA-1) and FLS CD54 (ICAM-1). Reduction of B7-H3 expression on FLS by RNA interference affected interactions of FLS with resting T cells or cytokine-activated T cells. Resting T cells showed increased production of TNF-α, IFN-γ, and IL-2, whereas cytokine-activated T cells showed reduced cytokine production relative to control. However, cytokine production by T cells activated through their TCR was not notably altered by knock down of B7-H3. These observations suggest that B7-H3 may be important for the interactions between FLS and T cells in RA, as well as other diseases, and the outcome of such interactions depends on the activation state of the T cell.

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“…B7-H3 is thought to serve as an accessory co-regulator of T-cell responses after initial antigen priming. At present, there is no consensus with regard to the physiological and pathological roles of B7-H3, as both immunological stimulatory and inhibitory functions have been described (Chapoval et al, 2001;Sun et al, 2002;Suh et al, 2003;Castriconi et al, 2004;Prasad et al, 2004;Steinberger et al, 2004;Wang et al, 2005;Zhang et al, 2005). It was originally identified as a co-stimulatory molecule that promotes T-cell proliferation and IFN-g production (Chapoval et al, 2001).…”

mentioning

confidence: 99%

Clinical importance of B7-H3 expression in human pancreatic cancer

et al. 2009

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BACKGROUND: B7-H3 is a new member of the B7 ligand family and regulates T-cell responses in various conditions. However, the role of B7-H3 in tumour immunity is largely unknown. The purpose of this study was to evaluate the clinical significance of B7-H3 expression in human pancreatic cancer and the therapeutic potential for cancer immunotherapy. METHODS: We investigated B7-H3 expression in 59 patients with pancreatic cancer by immunohistochemistry and real-time PCR. Furthermore, we examined the anti-tumour effect of B7-H3-blocking monoclonal antibody in vivo in a murine pancreatic cancer model. RESULTS: Tumour-related B7-H3 expression was abundant in most human pancreatic cancer tissues and was significantly higher compared with that in non-cancer tissue or normal pancreas. Moreover, its expression was significantly more intense in cases with lymph node metastasis and advanced pathological stage. B7-H3 blockade promoted CD8 þ T-cell infiltration into the tumour and induced a substantial anti-tumour effect on murine pancreatic cancer. In addition, the combination of gemcitabine with B7-H3 blockade showed a synergistic anti-tumour effect without overt toxicity. CONCLUSION: Our data show for the first time that B7-H3 may have a critical role in pancreatic cancer and provide the rationale for developing a novel cancer immunotherapy against this fatal disease.

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Murine B7-H3 Is a Negative Regulator of T Cells

Cited by 299 publications

References 44 publications

B7‐H3 promotes acute and chronic allograft rejection

B7‐H3 promotes acute and chronic allograft rejection

Interactions of T Cells with Fibroblast-Like Synoviocytes: Role of the B7 Family Costimulatory Ligand B7-H3

Clinical importance of B7-H3 expression in human pancreatic cancer

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