Expression of mouse interleukin-4 by a recombinant ectromelia virus suppresses cytolytic lymphocyte responses and overcomes genetic resistance to mousepox

Abstract

Genetic resistance to clinical mousepox (ectromelia virus) varies among inbred laboratory mice and is characterized by an effective natural killer (NK) response and the early onset of a strong CD8(+) cytotoxic T-lymphocyte (CTL) response in resistant mice. We have investigated the influence of virus-expressed mouse interleukin-4 (IL-4) on the cell-mediated response during infection. It was observed that expression of IL-4 by a thymidine kinase-positive ectromelia virus suppressed cytolytic responses of NK and CTL and the expression of gamma interferon by the latter. Genetically resistant mice infected with the IL-4-expressing virus developed symptoms of acute mousepox accompanied by high mortality, similar to the disease seen when genetically sensitive mice are infected with the virulent Moscow strain. Strikingly, infection of recently immunized genetically resistant mice with the virus expressing IL-4 also resulted in significant mortality due to fulminant mousepox. These data therefore suggest that virus-encoded IL-4 not only suppresses primary antiviral cell-mediated immune responses but also can inhibit the expression of immune memory responses.

FIG. 1

(A) Antiorthopoxvirus CTL responses in C57BL/6 mice following footpad inoculation with various doses of ECTV-IL4(TK+) or ECTV-602(TK+). Lytic activity of splenocytes taken 7 days p.i. was determined at different effector-to-target ratios. Data shown are representative of two assays carried out in triplicate with four mice per group. Standard errors of the means at all points were <5%. (B) NK cell response in C57BL/6 mice following footpad inoculation with 10⁴ PFU of ECTV-IL4(TK+) or ECTV-602(TK+) 3 days p.i. Lytic activities at different effector-to-target ratios are shown. Data shown are representative of two assays carried out in triplicate with four mice per group. Standard errors of the means at all points were <5%.