Tumor necrosis factormediated survival of CD169⁺ cells promotes immune activation during vesicular stomatitis virus infection

Innate immune activation is essential to mount an effective antiviral response and to prime adaptive immunity. Although a crucial role of CD169⁺ cells during vesicular stomatitis virus (VSV) infections is increasingly recognized, factors regulating CD169⁺ cells during viral infections remain unclear. Here, we show that tumor necrosis factor is produced by CD11b⁺ Ly6C⁺ Ly6G⁺ cells following infection with VSV. The absence of TNF or TNF receptor 1 (TNFR1) resulted in reduced numbers of CD169⁺ cells and in reduced type I interferon (IFN-I) production during VSV infection, with a severe disease outcome. Specifically, TNF triggered RelA translocation into the nuclei of CD169⁺ cells; this translocation was inhibited when the paracaspase MALT-1 was absent. Consequently, MALT1 deficiency resulted in reduced VSV replication, defective innate immune activation, and development of severe disease. These findings indicate that TNF mediates the maintenance of CD169⁺ cells and innate and adaptive immune activation during VSV infection.