The myxoma virus TNF-receptor homologue (T2) inhibits tumor necrosis factor-α in a species-specific fashion

The myxoma virus T2 protein shares extensive homology with the ligand binding domains of tumor necrosis factor (TNF) receptors. To characterize the T2-TNF interaction, myxoma T2 protein and rabbit, mouse, and human TNFα were expressed independently from vaccinia virus vectors. Growth of the TNFα-expressing viruses was significantly attenuated in TNF-hypersensitive L929-8 cells, and these cells were rapidly lysed by all three TNFαs. Rabbit cells showed strict species specificity in that RK-13 and SIRC cells were only sensitive to lysis by the homologous rabbit TNFα. Although RK-13 cells were hypersensitive to rabbit TNFα even in the absence of protein synthesis inhibitors, growth of T2 nonexpressing myxoma and vaccinia viruses in RK-13 cells was only modestly reduced in the presence of rabbit TNFα, suggesting that poxviruses possess additional anti-TNF mechanisms. When the ability of the myxoma T2 protein to inhibit biological activities of TNFα was assayed, T2 protein effectively protected L929-8 cells from lysis by rabbit, but not human or mouse TNFα. These studies show that rabbit TNF receptors may be species-specific for rabbit TNFα and we conclude that the myxoma T2 protein evolved to specifically inhibit TNF activities from its natural host, the South American rabbit.