Depletion of CD4(+) T cells precipitates immunopathology in immunodeficient mice infected with a noncytocidal virus

IFN-gamma -deficient (IFN-gamma (-/-)) mice inoculated with intermediate do ses of a slowly replicating strain of lymphocytic choriomeningitis virus be come chronically infected. In such mice a hypercompensated CTL response is observed that partially controls virus replication. Here we have investigat ed whether CD4(+) Th cells are required to establish and maintain this new equilibrium. The absence of IFN-gamma does not impair the generation of IL- 2-producing CD4(+) cells, and depletion of these cells precipitates severe CD8(+) T cell-mediated immunopathology in IFN-gamma (-/-) mice, indicating an important role of CD4(+) T cells in preventing this syndrome. Analysis o f organ virus levels revealed a further impairment of virus control in IFN- gamma (-/-) mice following CD4(+) cell depletion. Initially the antiviral C TL response did not require CD4(+) cells, but with time an impaired reactiv ity toward especially the glycoprotein 33-41 epitope was noted. Enumeration of epitope-specific (glycoprotein 33-41 and nucleoprotein 396-404) CD8(+) T cells by use of tetramers gave similar results. Finally, limiting dilutio n analysis of CTL precursors reveal an impaired capacity to sustain this po pulation in CD4(+)-depleted mice, especially in mice also deficient in IFN- gamma. Thus, our findings disclose that T cell help is required to sustain the expanded CTL precursor pool required in IFN-gamma (-/-) mice. This inte rpretation is supported by mathematical modeling that predicts an increased requirement for help in IFN-gamma (-/-) hosts similar to what is found wit h fast replicating virus strains in normal hosts. Thus, the functional inte grity of CD8+ effector T cells is one important factor influencing the requ irement for T cell help during viral infection.