Costimulating aberrant T cell responses by B7-H1 autoantibodies in rheumatoid arthritis
Haidong Dong, Scott E. Strome, Eric L. Matteson, Kevin G. Moder, Dallas B. Flies, Gefeng Zhu, Hideto Tamura, Colin L.W. Driscoll, Lieping Chen
Haidong Dong, Scott E. Strome, Eric L. Matteson, Kevin G. Moder, Dallas B. Flies, Gefeng Zhu, Hideto Tamura, Colin L.W. Driscoll, Lieping Chen
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Article Immunology

Costimulating aberrant T cell responses by B7-H1 autoantibodies in rheumatoid arthritis

Abstract

A pathogenic hallmark of rheumatoid arthritis (RA) is persistent activation of self-reactive CD4+ T cells. The cause of this aberrant activity remains elusive. We report here detection of autoantibodies against B7-H1, a recently described member of the B7 family, in 29% of patients with RA versus 4% of healthy donors. High-level expression of cell surface B7-H1 are found on activated human CD4+, CD8+, and CD45RO+ T cells. Immobilized autoantibodies to B7-H1 are capable of costimulating the proliferation of CD4+ T cells in vitro, and the presence of these autoantibodies correlates with active disease status. Using immobilized B7-H1 mAb’s and programmed death 1Ig, we demonstrate that engagement of B7-H1 on CD4+ T cells costimulates proliferation and secretion of IL-10, and subsequently leads to programmed cell death, accompanied with upregulated expression of TNF-related apoptosis–inducing ligand and activation of caspase-3. Taken together with our previous findings, these data indicate a bidirectional signaling role of B7-H1 in T cell costimulation and apoptosis and implicate B7-H1 autoantibodies as contributing to the progression of RA by inducing aberrant T cell responses.

Authors

Haidong Dong, Scott E. Strome, Eric L. Matteson, Kevin G. Moder, Dallas B. Flies, Gefeng Zhu, Hideto Tamura, Colin L.W. Driscoll, Lieping Chen

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B7-H1 mAb costimulates human CD4+ T cell proliferation. (a) Purified hum...
B7-H1 mAb costimulates human CD4+ T cell proliferation. (a) Purified human CD4+ T cells were cultured with immobilized 10 μg/ml of control (ctl) Ab, B7-H1 mAb (2H1), PD-1Ig, and 2 μg/ml of CD28 mAb in the presence of precoated different dose of CD3 mAb. Cultures were pulsed with 3H-TdR for a final 16 hours, and the cells were harvested at 72 hours. (b) Dose-dependent costimulation of immobilized anti–B7-H1 mAb in the presence of suboptimal dose (30 ng/ml) of CD3 mAb. Titration of mAb or fusion protein was started at 20 μg/ml of control Ab, B7-H1 mAb, PD-1Ig, and 4 μg/ml of CD28 mAb. (c) Human CD4+ T cells were costimulated with 20 μg/ml of soluble control (ctl) Ab, B7-H1 mAb (2H1), PD-1Ig, and 2 μg/ml of CD28 mAb as the same condition in a. (d) Blocking of B7-H1 mAb–mediated costimulation by soluble B7-H1Ig. Soluble control Ig, B7-1Ig, or B7-H1Ig (10 μg/ml) was preincubated with immobilized control (ctl) Ab or B7-H1 mAb (2H1) for 30 minutes before the addition of T cells. B7-H1 costimulation was assayed in the presence of suboptimal dose of CD3 mAb for 72 hours of culture. (e) FACS analysis of IL-2 receptor (CD25) expression in CD4+ T cells after B7-H1 mAb costimulation. (f) IL-10 secretion from CD4+ T cells in the presence of immobilized CD3 mAb (500 ng/ml), and B7-H1 mAb (10 μg/ml), or CD28 mAb (2 μg/ml).