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Published online before print April 7, 2005

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(Journal of Leukocyte Biology. 2005;78:266-278.)
© 2005 by Society for Leukocyte Biology

TNFR1-induced sphingomyelinase activation modulates TCR signaling by impairing store-operated Ca²⁺ influx

Leigh D. Church^*,1, Gabriele Hessler, John E. Goodall^*, David A. Rider^*, Creg J. Workman, Dario A. A. Vignali, Paul A. Bacon^*, Erich Gulbins and Stephen P. Young^*

^* Department of Rheumatology, Division of Immunity and Infection, University of Birmingham, United Kingdom;
Department of Molecular Biology, University of Duisburg-Essen, Germany; and
Department of Immunology, St. Jude Children’s Research Hospital, Memphis, Tennessee

¹ Correspondence: Department of Rheumatology, Division of Immunity and Infection, The Medical School, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK. E-mail: L.D.Church{at}Bham.ac.uk

Tumor necrosis factor (TNF-) is a potent, pleiotrophic cytokine, which is proinflammatory but can also suppress T lymphocyte function. In chronic inflammatory disease such as rheumatoid arthritis, exposure of T cells to TNF- alters their ability to mount a response by modulating the T cell receptor (TCR) signaling pathway, but the mechanisms involved remain obscure. Here, we investigated the specific role of TNF receptor 1 (TNFR1) signaling in the modulation of the TCR signaling pathway. We observed a down-regulation of the intracellular calcium ([Ca²⁺]_i) signal in Jurkat T cells after just 30 min exposure to TNF-, and maximum suppression was reached after 3 h. This effect was transient, and signals returned to normal after 12 h. This depression of [Ca²⁺]_i was also observed in human CD4+ T lymphocytes. The change in Ca²⁺ signal was related to a decrease in the plasma membrane Ca²⁺ influx, which was apparent even when the TCR signal was bypassed using thapsigargin to induce a Ca²⁺ influx. The role of TNF--induced activation of the sphingolipid cascade in this pathway was examined. The engagement of TNFR1 by TNF- led to a time-dependent increase in acid sphingomyelinase (SMase; ASM) activity, corresponding with a decrease in cellular sphingomyelin. In parallel, there was an increase in cellular ceramide, which correlated directly with the decrease in the magnitude of the Ca²⁺ response to phytohemagglutinin. Exogenous addition of SMase or ceramide mimicked the effects of TNFR1 signals on Ca²⁺ responses in Jurkat T cells. Direct evidence for the activation of ASM in this pathway was provided by complete abrogation of the TNF--induced inhibition of the Ca²⁺ influx in an ASM-deficient murine T cell line (OT-II^+/+ASM^–/–). This potent ability of TNF- to rapidly modulate the TCR Ca²⁺ signal via TNFR1-induced ASM activation can explain its suppressive effect on T cell function. This TNFR1 signaling pathway may play a role as an important regulator of T cell responses.

Key Words: T lymphocyte • T cell receptor • signal transduction • cytokines • lipid mediators

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