Tissue-specific expression of B7x protects from CD4 T cell–mediated autoimmunity

Wei, Joyce; Loke, P’ng; Zang, Xingxing; Allison, James P.

doi:10.1084/jem.20100639

Cited by 58 publications

(102 citation statements)

References 55 publications

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“…It remains unclear what roles B7-H4 play in the periphery, and whether it has functions that are independent of its effect on T cells. We and others have shown that the pancreas expresses moderate level of B7-H4, especially in the endocrine cells [25,27] . This raises the question of what the specific functions of B7-H4 are in pancreatic islets, and suggests the intriguing possibility that activity of B7-H4 is not limited to immune-modulation.…”

Section: B7-h4: a Novel Immune-regulatory Moleculementioning

confidence: 76%

“…Return of glycemic control was observed in newly-onset diabetic NOD mice following B7-H4 Ig injections [33] . Conversely, adoptive transfer of diabetogenic T cells into B7-H4 deficient mice resulted in more exacerbated disease than wild-type controls [27] . It was hypothesized that B7-H4 did not have an effect on recruitment of immune infiltrates during the pre-diabetic stage, but rather, it prevented the progression of insulitis to overt diabetes by arresting severe insulitis at 12 wk of age in NOD mice [27,31] .…”

Section: B7-h4 As a Protective Shield For β-Cells In T1dmentioning

confidence: 90%

“…As a negative cosignaling molecule, B7-H4 has the potential to downregulate autoreactivity in autoimmune diseases such as T1D. While B7-H4 deficiency itself does not cause autoimmune diseases, various studies showed that B7-H4 plays an important role in inhibition of auto-reactive T cells in diseases such as experimental autoimmune encephalomyelitis, and rheumatoid arthritis [22,27] . Genome-wide association studies have also uncovered certain Single Nucleotide Polymorphisms within the B7-H4-encoding VTCN1 gene as disease-causing in the context of diabetes, further implicating B7-H4 as a potential regulator of T1D [29] .…”

Section: B7-h4 As a Protective Shield For β-Cells In T1dmentioning

confidence: 99%

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B7-H4 as a protective shield for pancreatic islet beta cells

Sun

Luciani

et al. 2014

WJD

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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 cosignaling molecule B7-H4 which is expressed in normal human islets, and its expression co-localizes with insulin. A concomitant decrease in B7-H4/insulin colocalization 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.

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Section: B7-h4: a Novel Immune-regulatory Moleculementioning

confidence: 76%

Section: B7-h4 As a Protective Shield For β-Cells In T1dmentioning

confidence: 90%

Section: B7-h4 As a Protective Shield For β-Cells In T1dmentioning

confidence: 99%

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B7-H4 as a protective shield for pancreatic islet beta cells

Sun

Luciani

et al. 2014

WJD

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“…It is possible that abundant B7-H4 proteins on the surface of tumor cells can impair the effector functions of tumor-infiltrating lymphocytes akin to a molecular shield model proposed for PD-L1 (45,46). In support of this concept, it has been shown that the quantity of B7-H4 on the surface of pancreatic b cells positively correlates with their resistance to T cell attack in murine models of type I diabetes (9). However, our data have shown that, regardless of tumor B7-H4 expression, host B7-H4 still contributes to differences in both proand antitumor immune components, which drives the differences observed in immunoediting between WT and B7-H4 KO mice.…”

Section: Discussionmentioning

confidence: 95%

“…Functionally, engagement of the putative, unidentified B7-H4 receptor on T cells with recombinant B7-H4-Fc proteins in vitro reduced CD4 and CD8 T cell proliferation and cytokine production (1)(2)(3)7). Consistently, B7-H4 knockout (KO) mice displayed elevated Th1 responses against Leishmania major (8) and enhanced Th1 and Th17 responses to experimental autoimmune diseases (9). Interestingly, B7-H4 has also been shown to negatively regulate neutrophil-mediated innate immune responses.…”

mentioning

confidence: 95%

Host B7-H4 Regulates Antitumor T Cell Responses through Inhibition of Myeloid-Derived Suppressor Cells in a 4T1 Tumor Transplantation Model

Leung

Suh

2013

The Journal of Immunology

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B7-H4, a member of the B7 family of T cell immunomodulatory proteins, has been shown to inhibit T cell responses and neutrophil expansion during bacterial infections. However, the role of B7-H4 in the immune response during tumor growth has been unclear. In this study, we examined the host immune responses in B7-H4–deficient (knockout [KO]) or sufficient (wild-type [WT]) BALB/cJ mice upon transplantation of murine 4T1 carcinoma cells that had little B7-H4 expression. We reveal that host B7-H4 not only dampens the antitumor Th1 responses, but also inhibits the protumor function of myeloid-derived suppressor cells (MDSC). We observed increased expression of both antitumor immune effectors and protumor MDSC-associated transcripts in 4T1 tumors grown in B7-H4 KO mice compared with those grown in WT hosts. Consistently, MDSCs derived from B7-H4 KO mice suppressed T cell proliferation more potently than their WT counterparts. Although the primary growth of 4T1 tumors in B7-H4 KO hosts was similar to that in WT mice, tumors that had grown in B7-H4 KO hosts grew much slower than those from WT mice when subsequently transplanted into WT hosts. Importantly, this differential tumor growth during the secondary transplantation was abrogated when recipient mice lacked T cells, indicating that the immune environment in B7-H4 KO hosts allowed outgrowth of 4T1 tumors with reduced immune-evasive capacities against T cells. Thus, B7-H4 can inhibit both antitumor T cells and protumor MDSCs, influencing the immune-evasive character of the outgrowing tumors. These factors should be considered if B7-H4 blockade is to be used for cancer immunotherapy.

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