B Cell-Specific Expression of Inducible Costimulator Ligand Is Necessary for the Induction of Arthritis in Mice

Objective. Inducible costimulator (ICOS)-ICOSL interactions are necessary for activation of Teff cells and follicular helper T (Tfh) cells. ICOSL is expressed on B cells, macrophages, and dendritic cells and can be induced on nonhematopoietic cells. The aim of this study was to determine whether expression of ICOSL on B cells is necessary for the development of proteoglycan (PG)-induced arthritis (PGIA). Methods. PGIA was initiated by immunizing wildtype and ICOSL-deficient (ICOSL-/-) or B cell-specific ICOSL-/- chimeric BALB/c mice with human PG in adjuvant. The onset and severity of arthritis were monitored over time. CD4+ T cell proliferation and CD4+ T cell cytokine production were measured in vitro after the cells were restimulated with PG. Germinal center (GC) B cells, plasma cells, Tfh cells, and Treg cells were identified by staining with specific antibodies. Results. Arthritis progression was completely inhibited in both ICOSL-/- mice and B cell-specific ICOSL-/- chimeric mice. Production of the Teff cell-produced cytokines interferon-gamma and interleukin-17 (IL-17) and the antiinflammatory cytokine IL-4 was suppressed. The reduced percentages of GCs and Tfh cells and the decreased production of IL-21 correlated with a decrease in the anti-mouse PG antibody response. However, the percentage of plasma cells was not reduced despite a reduction in IgG responses. Conclusion. These data indicate that the signals provided by ICOSL-expressing B cells to Teff cells and Tfh cells are necessary for the development of arthritis. Thus, therapeutic blockade of ICOSL-ICOS interactions may be an effective strategy for the treatment of rheumatoid arthritis.