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
View: Text | PDF
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

×

Figure 4

Options: View larger image (or click on image) Download as PowerPoint
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.