Engagement of CD153 (CD30 ligand) by CD30+ T cells inhibits class switch DNA recombination and antibody production in human IgD+ IgM+ B cells

CD153 (CD30 ligand) is a member of the TNF ligand/cytokine family expressed on the surface of human B cells, Upon exposure to IL-4, a critical Ig class switch-inducing cytokine, Ag-activated T cells express CD30, the CD153 receptor. The observation that dysregulated IgG, IgA, and/or IgE production is often associated with up-regulation of T cell CD30 prompted us to test the hypothesis that engagement of B cell CD153 by T cell CD30 modulates Ig class switching. In this study, we show that IgD(+) IgM(+) B cells up-regulate CD153 in the presence of CD154 (CD40 ligand), IL-4, and B cell Ag receptor engagement. In these cells, CD153 engagement by an agonistic anti-CD153 mAb or T cell CD30 inhibits S mu->S gamma, S mu->S alpha, and S mu->S epsilon class switch DNA recombination (CSR), This inhibition is associated with decreased TNFR-associated factor-2 binding to CD40, decreased NF-KB binding to the CD40-responsive element of the C gamma 3 promoter, decreased I gamma 3-C gamma 3 germline gene transcription, and decreased expression of Ku70, Ku80, DNA protein kinase, switch-associated protein-70, and Msh2 CSR-associated transcripts. In addition, CD153 engagement inhibits IgG, IgA, and IgE production, and this effect is associated with reduced levels of B lymphocyte maturation protein-1 transcripts, and increased binding of B cell-specific activation protein to the Ig 3' enhancer. These findings suggest that CD30(+) T cells modulate CSR as well as IgG, IgA, and IgE production by inducing reverse signaling through B cell CD153.