Co-inhibitory role of T-cell-associated B7-H1 and B7-DC in the T-cell immune response
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.
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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.).
References (25)
- et al.
B7+CTLA4+ T cells engage in T–T cell interactions that mediate apoptosis: a model for lentivirus-induced T cell depletion
Vet Immunol Immunopathol
(2004) - et al.
PD-1 ligands, negative regulators for activation of naive, memory, and recently activated human CD4+ T cells
Cell Immunol
(2004) Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity
Nat Rev
(2004)- et al.
The B7 family revisited
Annu Rev Immunol
(2005) - et al.
CD28/B7 system of T cell costimulation
Annu Rev Immunol
(1996) - et al.
Feline immunodeficiency virus (FIV) is characterized by B7+CTLA4+ T cell apoptosis
J Infect Dis
(2002) - et al.
B7 expression on T cells down-regulates immune responses through CTLA-4 ligation via R–T interactions
J Immunol
(2004) - et al.
Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation
J Exp Med
(2000) - et al.
Costimulating aberrant T cell responses by B7-H1 autoantibodies in rheumatoid arthritis
J Clin Invest
(2003) - et al.
Regulation of PD-1, PD-L1, and PD-L2 expression during normal and autoimmune responses
Eur J Immunol
(2003)