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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Detection, costimulatory function, and disease association of B7-H1 auto...
Detection, costimulatory function, and disease association of B7-H1 autoantibodies in RA patients. CD4+ T cells were cultured with immobilized (a) or soluble (b) sera IgG at the initiated dose of 20 μg/ml in the presence of suboptimal anti-CD3 mAb. The titers of RA 1 and RA 2 patients are 0.32 and 0.25 (OD450), respectively. (c) For blockade, the control (ctl) Ig, PD-1Ig, or B7-H1Ig at 3 μg/ml were added before the addition of CD4+ T cells. The growth of T cells was detected after 72 hours of culture. (d) To examine specificity of RA sera binding to B7-H1, diluted sera were preincubated with PBS, 2 μg/ml of soluble B7-H1Ig or control Ig (mIgG2a). (e) Diluted sera of 63 patients with RA and 54 healthy donors were tested for binding to B7-H1Ig by ELISA. Samples with OD450 values greater than 0.123 were considered positive. P value for differences between cohorts is shown (t test). (f) The sera at 1:1,000 dilution were examined for binding to B7-1Ig–coated vs. B7-H1Ig–coated ELISA plates. (g) Mock/624mel or B7-H1/624mel cells were stained with diluted (1:5) sera from 16 ELISA-positive RA patients. The inset bar shows the average percentage of positive staining. A typical histogram of FACS assay is shown on the left. (h) Sixty-three RA patients were sorted according to the active status of their disease, and the presence of B7-H1 autoantibodies. Statistical analysis of the correlation was performed as P = 0.0179 in a Fisher exact test.