TRANCE, a tumor necrosis factor family member critical for CD40 ligand-independent T helper cell activation

CD40 ligand (CD40L), a tumor necrosis factor (TNF) family member, plays a c ritical role in antigen-specific T cell responses in vivo. CD-COL expressed on activated CD4(+) T cells stimulates antigen-presenting cells such as de ndritic cells, resulting in the upregulation of costimulatory molecules and the production of various inflammatory cytokines required for CD4(+) T cel l priming in vivo. However, CD40L- or CD10-deficient mice challenged with v iruses 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 CD 4(+) T cell responses to viral infection were greatly diminished in CD40-de ficient 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 cost imulation required for efficient CD4(+) T cell priming during viral infecti on in the absence of CD40L/CD40. These results also indicate that not even the potent inflammatory microenvironment induced by viral infections is suf ficient to elicit efficient CD4(+) T cell priming without proper costimulat ion provided by the TNF family (CD40L or TRANCE). Moreover, the data sugges t that TRANCE/TRANCE-R may be a novel and important target for immune inter vention.