TCR-Independent CD30 Signaling Selectively Induces IL-13 Production Via a TNF Receptor-Associated Factor/p38 Mitogen-Activated Protein Kinase-Dependent Mechanism

Abstract

Initiation of T lymphocyte responses to most Ags requires concurrent stimulation through the TCR and costimulatory receptors such as CD28. Following initial activation, secondary receptors are up-regulated that can costimulate T cells in concert with TCR engagement. One such receptor is the TNFR family member CD30. In this study, we report that unlike CD28, ligation of CD30 on normal effector T cells induces IL-13 production in the absence of concurrent TCR engagement. TCR-independent CD30-mediated IL-13 release correlated with activation of c-Jun N-terminal kinase, p38 mitogen-activated protein kinase (MAPK), and NF-κB, and was completely inhibited by the expression of a TNFR-associated factor 2 (TRAF2) dominant-negative transgene (TRAF2.DN-Tg), but not by that of an I-κBα dominant-negative transgene. In parallel, expression of the TRAF2.DN-Tg selectively prevented the induction of c-Jun N-terminal kinase and p38 MAPK, but not that of NF-κB. Furthermore, IL-13 production was reduced in a dose-dependent manner by the p38 MAPK inhibitor SB203580. Together, these results suggest that TCR-independent CD30-mediated production of IL-13 is triggered by association of CD30 with TRAF family members and subsequent activation of p38 MAPK. Inasmuch as IL-13 can promote airway inflammation and cancer progression, production of IL-13 in a TCR-independent manner has important pathological implications in vivo.

Amino acid copolymer-specific IL-10-secreting regulatory T cells that ameliorate autoimmune diseases in mice

“…CD30 expression has been reported to be expressed on activated T cells and to have a role in the regulation of cytokine secretion (20). Particularly interesting in the present context is the reported induction of IL-13 secretion after ligation of CD30 in the absence of TCR engagement (21). Correspondingly, CD30Ϫ/Ϫ mice were reported to have augmented T cell autoreactivity (22).…”

Inhibition of p38 mitogen-activated protein kinase unmasks a CD30-triggered apoptotic pathway in anaplastic large cell lymphoma cells

“…CD30 signaling activates nuclear factor nB (NF-nB; refs. 6 -9) as well as the p38, c-Jun-NH 2 -kinase, and extracellular signal-regulated kinase mitogen-activated protein kinase (MAPK) pathways (10,11). Recruitment of the TNFR-associated factors directly to the cytoplasmic domain of CD30 following ligand binding is critical for the activation of downstream signaling events (7 -9).…”

B Cell Induction of IL-13 Expression in NK Cells: Role of CD244 and SLAM-Associated Protein

“…The production of a Th2 cytokine by NK cells provides another source of cytokines for the alternative pathway of macrophage activation (10). The induction of T cell production of IL-13 may be mediated by other cytokines as well as cell surface ligands such as CD30L (11). NK cells can be also induced to produce IL-13 by cytokines such as IL-2 and IL-18 (5,12,13), but whether they can be stimulated by surface ligands expressed by other cell types is not known.…”