Elsevier

Immunology Letters

Volume 102, Issue 2, 15 February 2006, Pages 222-228
Immunology Letters

Co-inhibitory role of T-cell-associated B7-H1 and B7-DC in the T-cell immune response

https://doi.org/10.1016/j.imlet.2005.09.007Get rights and content

Abstract

B7-H1 and B7-DC expressed on antigen-presenting cells inhibit the T-cell response via the PD-1 counter–receptor on T cells, and co-stimulate T-cell immunity under certain conditions via an unidentified co-stimulatory receptor. However, little is known about the functional consequence of T-cell-associated B7-H1 or B7-DC in the T-cell immune response. Therefore, we evaluated the physiological role of B7-H1 and B7-DC expressed on T cells in terms of cell proliferation and cytokine production by alloreactive T cells. We found that PD-1, B7-H1, and B7-DC were up-regulated in alloreactive CD4+ and CD8+ T cells in vitro and in vivo. In the alloreactive T–T model, blockade of the B7-H1:PD-1 or B7-DC:PD-1 pathways significantly increased the proliferation, and IFN-γ and IL-2 production of alloreactive T cells, although it did not affect the production of other cytokines, including IL-4, IL-10, and IL-12. The data indicate that T-cell-associated B7-H1 and B7-DC negatively regulate the T-cell response via the T–T interaction.

Introduction

B7 co-signaling molecules are a group of glycoproteins that transmit intracellular biochemical signals via their respective receptors, which belong to the CD28 family, leading to the fine tuning of T-cell receptor (TCR) signaling [1]. B7.1 (CD80) and B7.2 (CD86) expressed on antigen-presenting cells (APC) deliver a co-stimulatory signal to naïve T cells via CD28, and a co-inhibitory signal via CTLA-4 expressed on activated T cells [2]. B7.1 and B7.2 are expressed not only in APCs, including dendritic cells (DCs), macrophages, and activated B cells, but also in activated T cells [3], [4]. Recent studies indicate that B7.1 and B7.2 expressed on activated T cells interact with CTLA-4 on T cells, resulting in a high frequency of apoptosis of activated T cells in vitro and in vivo [5], [6].

B7-H1 (CD274) and B7-DC (CD273) are independent ligands that bind to the co-inhibitory PD-1 receptor or to an as-yet unidentified co-stimulatory receptor on T cells [7], [8]. Unlike the limited expression of B7.1/B7.2 by myeloid/lymphoid lineage cells, B7-H1 mRNA is expressed in cells from various tissues, including heart, liver, lung, and placenta, as well as in resting DCs, macrophages, and B cells, and its expression is up-regulated in vitro in response to inflammatory cytokines, including IFN-γ [9]. By contrast, B7-DC expression is limited more to DCs and macrophages than B7-H1 [10]. Similar to the expression profile of B7.1/B7.2, both B7-H1 and B7-DC are induced in T cells that have been activated by anti-CD3 antibody or exposed to an inflammatory microenvironment [9], [11]. Based on the pattern of B7-H1 and B7-DC expression in activated T cells, we hypothesized that T-cell-associated B7-H1 and B7-DC interact with PD-1 or another co-stimulatory receptor on T cells. Using an alloreactive T-cell model, we found that B7-H1 and B7-DC expression on T cells is a negative regulator of the T-cell response via the PD-1 pathway.

Section snippets

Mice

Balb/c (H-2d) and C57BL/6 (H-2b) mice were obtained from Charles River (Yokohama, Japan). All mice (7–10 weeks of age) were housed in accordance with institutional guidelines.

Antibodies

Antagonistic mouse B7-H1 mAb (10B5) and isotype control hamster anti-DNP (UC8-1B9) mAb were purified from ascites using a protein G-column (Sigma, St. Louis, MO). The binding activities of the mAbs were tested using spleen cells stimulated with lipopolysaccharide (LPS, 5 μg/ml) for 24 h or the mouse B7-H1 transfectant of 293

Role of polyclonally activated T-cell-associated B7-H1 and B7-DC in T-cell proliferation and cytokine production

First, we examined the expression of PD-1, B7-H1, and B7-DC in T cells following T-cell receptor (TCR)-mediated activation. Freshly isolated Thy1.2+ T cells were stimulated with anti-CD3 mAb and the expression of each was detected using flow cytometry. PD-1 expression was induced on T cells following anti-CD3 stimulation compared to naïve T cells (naïve 0.9 ± 0.1% versus induced 12.5 ± 1.7%). In parallel, both B7-H1 and B7-DC were also up-regulated in activated T cells. As shown in Fig. 1A, more

Discussion

The physiologic role of B7-H1 as a co-inhibitor ligand was evidenced by the findings that antagonistic B7-H1 mAb rapidly precipitated diabetes in NOD mice [16], and that B7-H1 Ig promoted cardiac and islet allografts survival [17], [18]. These observations may be explained by the ability of B7-H1 to interact with the co-inhibitory receptor PD-1 on T cells. Under some conditions, however, B7-H1 acts like a co-stimulator, in which the local expression of B7-H1 in pancreatic β cells promotes

Acknowledgments

This study was supported by National R&D Program Grant (M10417060006-04N1706-00610) of The Ministry of Science and Technology (I.-H. Choi), by the Korea Science and Engineering Foundation through National Research Laboratory Program Grant M10500000008-05J000000810 (Y.-M. Park), and by National Institutes of Health Grant CA97085 and CA106861 (L.C.).

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