Costimulating aberrant T cell responses by B7-H1 autoantibodies in rheumatoid arthritis
Haidong Dong, … , Colin L.W. Driscoll, Lieping Chen
Haidong Dong, … , Colin L.W. Driscoll, Lieping Chen
Published February 1, 2003
Citation Information: J Clin Invest. 2003;111(3):363-370. https://doi.org/10.1172/JCI16015.
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Categories: 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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Figure 4

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B7-H1 mAb promotes programmed cell death of activated CD4+ T cells. (a) ...
B7-H1 mAb promotes programmed cell death of activated CD4+ T cells. (a) Human CD4+ T cells were cultured with 10 μg/ml of immobilized control (ctl) Ab, B7-H1 mAb, PD-1Ig in the presence of precoated optimal dose (500 ng/ml) of CD3 mAb. The cells were analyzed by FACS to determine apoptotic cells (positive in AV and negative in PI staining). (b) Blocking of B7-H1 mAb-induced apoptosis by soluble B7-H1Ig. Control Ig or B7-H1Ig at 10 μg/ml was preincubated with immobilized control Ab or B7-H1 mAb for 30 minutes before the addition of T cells. Percentages of apoptotic CD4+ T cells were shown at 72 hours of culture. (c) Expression of apoptotic genes by B7-H1 mAb costimulation. Purified human CD4+ T cells (5 × 106) were cultured with immobilized B7-H1 mAb or control mAb at 10 μg/ml in the presence of optimal dose of CD3 mAb. The mRNA levels of each gene from B7-H1 mAb-stimulated T cells were presented as the fold induction, relevant to that from control mAb-treated T cells. (d) FACS analysis of expression of TRAIL protein on CD4+ T cells 3 days after anti-CD3/B7-H1 mAb costimulation. (e) Purified human CD4+ T cells were stimulated in the presence of indicated mAb or fusion protein in immobilized form as indicated in the legend of a and the activated form of caspase-3 at the indicated time point was stained by FAM-DEVD-FMK and subjected to FACS analysis. (f) Blocking of B7-H1 mAb-induced apoptosis of activated CD4+ T cells by anti–IL-10 neutralizing mAb. Purified human CD4+ T cells were stimulated with immobilized CD3 mAb and B7-H1 mAb for 72 hours, and the apoptotic cells were analyzed by AV and PI staining. Control Ab and mAbs to Fas ligand, IL-2, or IL-10 at 10 μg/ml was included at the beginning of the culture.