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Depletion of CD4⁺ T Cells Precipitates Immunopathology in Immunodeficient Mice Infected with a Noncytocidal Virus

Jan Pravsgaard Christensen^*, Christina Bartholdy^*, Dominik Wodarz and Allan Randrup Thomsen^2,*

^* Institute of Medical Microbiology and Immunology, University of Copenhagen, Copenhagen, Denmark; and Institute for Advanced Study, Princeton, NJ 08540

IFN--deficient (IFN-^-/-) mice inoculated with intermediate doses of a slowly replicating strain of lymphocytic choriomeningitis virus become chronically infected. In such mice a hypercompensated CTL response is observed that partially controls virus replication. Here we have investigated whether CD4⁺ Th cells are required to establish and maintain this new equilibrium. The absence of IFN- 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-^-/- mice, indicating an important role of CD4⁺ T cells in preventing this syndrome. Analysis of organ virus levels revealed a further impairment of virus control in IFN-^-/- mice following CD4⁺ cell depletion. Initially the antiviral CTL response did not require CD4⁺ cells, but with time an impaired reactivity 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 dilution analysis of CTL precursors reveal an impaired capacity to sustain this population in CD4⁺-depleted mice, especially in mice also deficient in IFN-. Thus, our findings disclose that T cell help is required to sustain the expanded CTL precursor pool required in IFN-^-/- mice. This interpretation is supported by mathematical modeling that predicts an increased requirement for help in IFN-^-/- hosts similar to what is found with fast replicating virus strains in normal hosts. Thus, the functional integrity of CD8⁺ effector T cells is one important factor influencing the requirement for T cell help during viral infection.

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