Cutting edge: induction of B7-H4 on APCs through IL-10: novel suppressive mode for regulatory T cells.

Department of Surgery, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA.
The Journal of Immunology (Impact Factor: 5.36). 08/2006; 177(1):40-4. DOI: 10.4049/jimmunol.177.1.40
Source: PubMed

ABSTRACT Multiple modes of suppressive mechanisms including IL-10 are thought to be implicated in CD4+CD25+ regulatory T (Treg) cell-mediated suppression. However, the cellular source, role, and molecular mechanism of IL-10 in Treg cell biology remain controversial. We now studied the interaction between Treg cells and APCs. We demonstrate that Treg cells, but not conventional T cells, trigger high levels of IL-10 production by APCs, stimulate APC B7-H4 expression, and render APCs immunosuppressive. Initial blockade of B7-H4 reduces the suppressive activity mediated by Treg cell-conditioned APCs. Further, APC-derived, rather than Treg cell-derived, IL-10 is responsible for APC B7-H4 induction. Therefore, Treg cells convey suppressive activity to APCs by stimulating B7-H4 expression through IL-10. Altogether, our data provide a novel cellular and molecular mechanism for Treg cell-mediated immunosuppression at the level of APCs, and suggest a plausible mechanism for the suppressive effect of IL-10 in Treg cell-mediated suppression.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Auto- and alloreactive T cells are major culprits that damage β-cells in type 1 diabetes (T1D) and islet transplantation. Current immunosuppressive drugs can alleviate immune-mediated attacks on islets. T cell co-stimulation blockade has shown great promise in autoimmunity and transplantation as it solely targets activated T cells, and therefore avoids toxicity of current immunosuppressive drugs. An attractive approach is offered by the newly-identified negative T cell co-signaling molecule B7-H4 which is expressed in normal human islets, and its expression co-localizes with insulin. A concomitant decrease in B7-H4/insulin co-localization is observed in human type 1 diabetic islets. B7-H4 may play protective roles in the pancreatic islets, preserving their function and survival. In this review we outline the protective effect of B7-H4 in the contexts of T1D, islet cell transplantation, and potentially type 2 diabetes. Current evidence offers encouraging data regarding the role of B7-H4 in reversal of autoimmune diabetes and donor-specific islet allograft tolerance. Additionally, unique expression of B7-H4 may serve as a potential biomarker for the development of T1D. Future studies should continue to focus on the islet-specific effects of B7-H4 with emphasis on mechanistic pathways in order to promote B7-H4 as a potential therapy and cure for T1D.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Unleashing the immune system to fight cancer has become one of the main treatment modalities since the anti-CTLA-4 antibody, ipilimumab was approved for patients with advanced melanoma in 2011. Pembrolizumab and nivolumab, two anti-PD-1 antibodies recently approved for the treatment of patients with metastatic melanoma, are being actively investigated for the treatment of multiple caners including lung, breast, bladder and renal cancers along with other anti-PD-1/L1 antibodies. Early results of combining of anti-CTLA-4 antibody and anti-PD-1 antibody treatment for advanced melanoma patients are showing impressive response rates with manageable toxicity profiles. There are several other checkpoint molecules that are likely potential inhibitory targets. The outcome of blocking some of these negative immune regulators, such as LAG-3 or TIM-3, is being pursued in the clinic or about to enter clinical development. Blockade of these molecules is demonstrating promising preclinical activity alone or when combined with anti-PD-1/L1. Future studies will define bio-markers of these therapies and how to target them alone or in combination with other immunotherapies, chemotherapy, radiotherapy and small molecule inhibitors.
    Current Opinion in Immunology 04/2015; 33. DOI:10.1016/j.coi.2015.01.006 · 7.87 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: B7-H4 is a recently identified member of the B7 family considered to negatively regulate the immune response, and has been associated with the occurrence and development of certain types of tumor. However, little is known regarding the importance of human B7-H4 expression in bladder urothelial carcinoma. In the present study, B7-H4 expression in the tissues and sera of patients with bladder urothelial carcinoma was investigated, along with the clinical significance. In addition, the effects of activated T-lymphocyte in vitro cytotoxicity in the BIU-87 bladder cancer cell line following the blockade of the B7-H4 signaling pathway were also analyzed. The results showed that in normal bladder tissues, B7-H4 was not detected, but in the bladder urothelial carcinoma tissue samples, B7-H4 was detected in 24/49 (49.0%) specimens. Additionally, positive B7-H4 expression was significantly associated with increased TNM stage and pathological grade (P<0.05). Compared with the healthy control group, the serum-B7-H4 (sB7-H4) concentrations in the patients were also significantly increased (P<0.05). The sB7-H4 concentrations in cases with high-grade histology were significantly higher than those in patients with low-grade histology (P<0.05). Following the blockade of the B7-H4 antigen in BIU-87 cells, the cytotoxic activity of activated T cells against such BIU-87 cells was significantly enhanced compared with that against the control BIU-87 cells. This occurred in a T cell density-dependent and blocking antibody dose-dependent manner. These observations suggest that B7-H4 is involved in tumor occurrence, and the development and immune escape of bladder urothelial carcinoma cells. Therefore, B7-H4 may be an important target in the diagnosis and/or treatment of bladder urothelial carcinoma.
    Oncology letters 12/2014; 8(6):2527-2534. DOI:10.3892/ol.2014.2522 · 0.99 Impact Factor


Available from