Impaired virus control and severe CD8+ T-cell-mediated immunopathology in chimeric mice deficient in gamma interferon receptor expression on both parenchymal and hematopoietic cells

Abstract

Bone marrow chimeras were used to determine the cellular target(s) for the antiviral activity of gamma interferon (IFN-gamma). By transfusing such mice with high numbers of naive virus-specific CD8(+) T cells, a system was created in which the majority of virus-specific CD8(+) T cells would be capable of responding to IFN-gamma, but expression of the relevant receptor on non-T cells could be experimentally controlled. Only when the IFN-gamma receptor is absent on both radioresistant parenchymal and bone marrow-derived cells will chimeric mice challenged with a highly invasive, noncytolytic virus completely lack the ability to control the infection and develop severe wasting disease. Further, the study shows that IFN-gamma receptor expression on parenchymal cells in the viscera is more important for virus control than IFN-gamma receptor expression on bone marrow-derived cells.

FIG. 1.

Adoptive transfer of naïve TCR-tg cells rescues IFN-γ^−/− mice, but not IFN-γR^−/− mice. IFN-γ^−/−, IFN-γR^−/−, and WT mice were infected i.v. with 10³ LD₅₀ LCMV Traub. Survival (A) and virus-induced weight loss (C) were followed until day 12 postinfection (5 to 10 mice/group). One day prior to virus challenge, part of the IFN-γ^−/− and IFN-γ R^−/− mice received 3 × 10⁶ donor cells from TCR-tg mice i.v. Survival (B) and virus-induced weight loss (D) were followed (5 mice/group). Changes in body weights are presented as median percentages of 5 to 10 mice/group. *, statistically significant differences at P < 0.05 (Mann-Whitney U test); †, too few observations for statistical analysis.

FIG. 2.

Adoptive transfer of naïve TCR-tg cells reestablishes virus control in IFN-γ^−/− mice, but not in IFN-γR^−/− mice. IFN-γ^−/−, IFN-γR^−/−, and WT mice were infected intravenously with 10³ LD₅₀ LCMV Traub. One day prior to virus challenge, part of the IFN-γ^−/− and IFN-γR^−/− mice received 3 × 10⁶ cells from TCR-tg mice i.v. The mice were sacrificed day 8 postinfection, and virus titers in spleens and livers were determined. Points represent individual mice. Dashed lines indicate the detection limit. *, statistically significant differences at P < 0.05 (Mann-Whitney U test).

FIG. 3.

Severe wasting disease and complete impairment of virus clearance in chimeric mice lacking IFN-γR expression in the hematopoietic and parenchymal compartments. Syngeneic and allogeneic chimeras were constructed from IFN-γR^−/− and WT mice. Lethally irradiated (900 rads) mice received 20 × 10⁶ bone marrow cells (BM) intravenously. Eight weeks later the chimeras were given 3 × 10⁶ cells from TCR-tg mice and then challenged with 10³ LD₅₀ LCMV Traub i.v. 1 day later. The mice (10 mice/group) were weighed daily until day 10 postinfection; medians of the changes in body weight are presented (A). Spleens and livers were harvested day 10 postinfection, and the virus titers were determined; points represent individual mice (B). The lower dashed lines indicate the detection limit, and the upper dashed lines indicate the medians of organ virus titers in unmanipulated IFN-γR^−/− mice challenged with 10³ LD₅₀ of LCMV Traub. *, statistically significant differences at P < 0,05 (Mann-Whitney U test).