DISTINCT DOMAINS OF M-T2, THE MYXOMA VIRUS TUMOR-NECROSIS-FACTOR (TNF) RECEPTOR HOMOLOG, MEDIATE EXTRACELLULAR TNF BINDING AND INTRACELLULAR APOPTOSIS INHIBITION

The myxoma virus tumor necrosis factor (TNF) receptor homolog, M-T2, i s expressed both as a secreted glycoprotein that inhibits the cytolyti c activity of rabbit TNF-alpha and as an endoglycosidase H-sensitive i ntracellular species that prevents myxoma virus-infected CD4(+) T lymp hocytes from undergoing apoptosis, To compare the domains of M-T2 medi ating extracellular TNF inhibition and intracellular apoptosis inhibit ion, recombinant myxoma viruses expressing nested C-terminal truncatio ns of M-T2 protein were constructed. One mutant, Delta L113, containin g intact copies of only two cysteine-rich domains, was not secreted an d was incapable of binding rabbit TNF-or yet retained full ability to inhibit virus-induced apoptosis of RL-5 cells, Thus, the minimal domai n of intracellular M-T2 protein required to inhibit apoptosis is disti nct from that required by the extracellular M-T2 for functional TNF-al pha binding and inhibition. This is the first report of a virus-encode d immunomodular protein with two distinct antiimmune properties.