Engagement of CD153 (CD30 Ligand) by CD30+ T Cells Inhibits Class Switch DNA Recombination and Antibody Production in Human IgD+ IgM+ B Cells

Abstract

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 Sμ→Sγ, Sμ→Sα, and Sμ→Sε class switch DNA recombination (CSR). This inhibition is associated with decreased TNFR-associated factor-2 binding to CD40, decreased NF-κB binding to the CD40-responsive element of the Cγ3 promoter, decreased Iγ3-Cγ3 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.

CD30 triggering by agonistic antibodies regulates CXCR4 expression and CXCL12 chemotactic activity in the cell line L540

“…on April 2, 2019. by guest www.bloodjournal.org From Thus, engagement of CD30 by CD153, which is associated preferentially with Th2-type effector responses, 19 regulates CXCR4 and CCR7 27 expression and delivers inhibitory signals, 20,27 leading to impaired clonal expansion of peripheral T cells, 21 sensitizing to TNFR1-dependent apoptosis, 3 and counteracting IgG and IgA production. 52 This cellularlevel regulation seems to have a counterpart in a number of conditions, sharing the tendency to selective compartmentalization of lowproliferating CD30 ϩ cells, which deliver locally anti-inflammatory cytokines, such as IL-4 and IL-10, whenever tested for 16 and which generate a molecular milieu characterized by features of immune suppression. 16,20 These conditions include autoimmune diabetes in mouse models, 21 rheumatoid arthritis, 16 Omenn syndrome, 14 a severe immunodeficiency characterized by features reminiscent of a Th2-type response in which large proportions of tissue-infiltrating CD30 ϩ cells are present, measles 53 in which CD30 ϩ cell expansion is related to the impaired mitogenic capability of T lymphocytes, inadequate Th1-type responses, and cell recruitment to lymph nodes and skin.…”

Clinical implications of the tumor necrosis factor family in benign and malignant hematologic disorders

“…Proposed physiologic functions of CD30L include a role in T-cell costimulation, cytokine and chemokine secretion, regulation of class-switch DNA recombination, and antibody production in subsets of human B cells. 23,24 CD30L has diverse biologic activity in different CD30ϩ cancers, ranging from enhancement of survival to no induction of apoptosis and cell cycle arrest. 14,[25][26][27][28][29] These paradoxical effects are caused by a differential effect on NF-B activation.…”

Mouse T cells receive costimulatory signals from LIGHT, a TNF family member

“…Cayabyab et al 10 and Van Essen et al 11 have shown that CD40L transduces costimulation signals into T cells. Wiley et al 12 have reported that CD30L cross-linking activates neutrophils, and Cerutti et al 13 showed that such reverse signaling inhibits the immunoglobin class switch in B cells. Reverse signaling through membrane TNF-␣ confers resistance of monocytes and macrophages to lipopolysaccharide.…”

“…3,20 Mouse TR6 has not been cloned. Human TR6 has 3 known ligands, FasL, 13 LIGHT, 3,4 and TL1A. 21 FasL binding by TR6 interferes with the interaction between Fas and FasL.…”