CD4(+) T cell-mediated control of a gamma-herpesvirus in B cell-deficient mice is mediated by IFN-gamma

Abstract

The lack of B cells and antibody does not prevent mice from dealing effectively with a pathogenic gamma-herpesvirus. Both CD4(+) and CD8(+) T cells contribute to the control of virus replication in the respiratory tract, with the depletion of either lymphocyte subset leading to increased titers in the lung. However, the further neutralization of IFN-gamma diminishes the effectiveness of the CD4(+) T cell response and causes substantially increased mortality. Experiments with bone marrow radiation chimeras indicate that the immune CD4(+) effectors operate optimally when there is the potential for direct interaction with virus-infected targets expressing MHC class II glycoproteins, suggesting that the IFN-gamma produced by these lymphocytes is functioning at short range. The numbers of latently infected cells in the spleens of carrier mice are also significantly increased by the concurrent depletion of both the CD4(+) population and IFN-gamma. These experiments raise the possibility that the defective control of intercurrent gamma-herpesvirus infections in patients with AIDS not only is due solely to the absence of helper T cells but also reflects the loss of an important set of CD4(+) effectors.

Figure 1

Control of the respiratory phase of MHV-68 infection by T cells and IFN-γ. The Ig^−/− μMT mice were dosed i.p. (27, 29, 32) with the GK1.5 (CD4), 2.43 (CD8), or XMG1.2 (IFN-γ) mAbs, starting 2 days prior to i.n. challenge with 600 pfu of MHV-68. The data are compiled from two experiments, giving final group sizes of 12 mice. The values in the parentheses show the percentage mortality prior to time of sampling on day 21 after virus challenge.

Figure 2

Neutralization of IFN-γ in the fluid phase obtained by BAL (27) from μMT mice challenged 14 days previously with MHV-68. Treatment with the XMG1.2 mAb (29) was begun 2 days prior to i.n. infection with 600 pfu of virus and then continued every second day until time of sampling. The numbers given are for individual mice, and the sensitivity of the ELISA was 15 pg/ml.

Figure 3

The magnitude of the CD4⁺ and CD8⁺ T cell responses in spleen (A and D) and the extent of depletion following treatment with the 2.43 mAb to CD8 (B and E) is shown for μMT → B6 (A and B) and μMT → C2D (D and E) chimeras at 21 days after i.n. infection with MHV-68. In both cases, the predominant CD4⁺ T cell population in mice lacking the CD8⁺ subset showed the activated CD44^high CD62L^low phenotype (C and F, Lower Right). The μMT → B6 mice have the potential to express the MHC class II glycoproteins that target the CD4⁺ subset in the radiation sensitive (μMT) and radiation-resistant (B6) compartments, whereas only cells of recent hemopoietic origin (μMT) could be MHC class II⁺ stimulators in the μMT → C2D chimeras.