The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1999/4/1025/ $5.00
The Journal of Experimental Medicine, Volume 189, Number 7, April 5, 1999 1025-1031

Articles

TRANCE, a Tumor Necrosis Factor Family Member Critical for CD40 Ligand–independent T Helper Cell Activation

Martin F. Bachmann*, Brian R. Wong||, Régis Josien§, Ralph M. Steinman§, Annette Oxenius{ddagger}, and Yongwon Choi||,¶

From the * Basel Institute for Immunology, CH 4005 Basel, Switzerland; the {ddagger} Institute for Experimental Immunology, 8019 Zürich, Switzerland; and the § Laboratory of Cellular Physiology and Immunology, the || Laboratory of Immunology, and the Howard Hughes Medical Institute, The Rockefeller University, New York 10021

CD40 ligand (CD40L), a tumor necrosis factor (TNF) family member, plays a critical role in antigen-specific T cell responses in vivo. CD40L expressed on activated CD4+ T cells stimulates antigen-presenting cells such as dendritic cells, resulting in the upregulation of costimulatory molecules and the production of various inflammatory cytokines required for CD4+ T cell priming in vivo. However, CD40L- or CD40-deficient mice challenged with viruses mount protective CD4+ T cell responses that produce normal levels of interferon {gamma}, suggesting a CD40L/CD40-independent mechanism of CD4+ T cell priming that to date has not been elucidated. Here we show that CD4+ T cell responses to viral infection were greatly diminished in CD40-deficient mice by administration of a soluble form of TNF-related activation-induced cytokine receptor (TRANCE-R) to inhibit the function of another TNF family member, TRANCE. Thus, the TRANCE/TRANCE-R interaction provides costimulation required for efficient CD4+ T cell priming during viral infection in the absence of CD40L/CD40. These results also indicate that not even the potent inflammatory microenvironment induced by viral infections is sufficient to elicit efficient CD4+ T cell priming without proper costimulation provided by the TNF family (CD40L or TRANCE). Moreover, the data suggest that TRANCE/TRANCE-R may be a novel and important target for immune intervention.

Key Words: TRANCE • CD40 ligand • T cell • dendritic cell • virus

Address correspondence to Martin F. Bachmann, Basel Institute for Immunology, Grenzacherstrasse 487, CH 4005 Basel, Switzerland. Phone: 41-61-605-1228; Fax: 41-61-605-1364; E-mail: bachmann{at}bii.ch; or to Yongwon Choi, Laboratory of Immunology, The Rockefeller University, 1230 York Ave., New York, NY 10021. Phone: 212-327-7441; Fax: 212-327-7319; E-mail: choi{at}rockvax.rockefeller.edu

The Basel Institute for Immunology was founded and is supported by F. Hoffmann-La Roche, Basel, Switzerland. This work was supported in part by National Institutes of Health Medical Scientist Training Program grant GM-07739 (to B.R. Wong), and National Institutes of Health grants AI-44264 (to Y. Choi), AI-13013 (to R.M. Steinman), and AI-39672 (to R.M. Steinman). R. Josien is supported by a fellowship from the Revson Foundation. Y. Choi is an investigator of the Howard Hughes Medical Institute.

Abbreviations used: DC, dendritic cell; GC, germinal center; LCMV, lymphocytic choriomeningitis virus; TRANCE, TNF-related activation-induced cytokine.


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