The zona pellucida (ZP), an ovarian extracellular structure, contains three major
glycoproteins: ZP1, ZP2, and ZP3. A ZP3
peptide contains both an
autoimmune oophoritis-inducing
T cell epitope and a
B cell epitope that induces
autoantibody to ZP. This study investigates two major T cell costimulation pathways in this disease model. Herein we show that blockage of
glycoprotein (gp)39 and CD40 interaction with gp39
monoclonal antibody (mAb) results in the failure to induce both
autoimmune oophoritis and
autoantibody production. Inhibition of
ligand binding to the CD28 receptor with the fusion
protein, murine CTLA4-immunoglobulin (Ig), also results in failure to generate antibody to ZP and significantly reduces disease severity and prevalence. Surprisingly, the frequencies of
antigen-specific T cells in anti-gp39 mAb-treated mice,
CTLA4-Ig treated mice, and in mice given control hamster
IgG or control fusion
protein L6, were equivalent as determined by limiting dilution analysis (approximately equals 1:5,000). These T cells, which produced comparable amounts of
interleukin 4 and
interferon gamma in vitro, were able to transfer
oophoritis to normal recipients. When anti-gp39 mAb and
CTLA4-Ig were given together, the effect was additive, leading to inhibition of T cell activation as determined by in vitro proliferation and limiting dilution analysis (approximately equals 1:190,000); disease and antibody responses were absent in these mice. By studying these two costimulatory pathways in parallel, we have shown that
autoimmune disease and
autoantibody production are inhibitable by blocking either the gp39 or the CD28 pathway, whereas inhibition of clonal expansion of the effector T cell population occurs only when both pathways are blocked.