CD4 + T Cells Develop Antiretroviral Cytotoxic Activity in the Absence of Regulatory T Cells and CD8 + T Cells

Abstract

Conventional CD4 + T cells play an important role in viral immunity. In most virus infections, they provide essential help for antiviral B and T cell responses. In chronic infections, including HIV infection, an expansion of regulatory T cells (Tregs) has been demonstrated, which can suppress virus-specific CD4 + T cell responses in vitro . However, the suppressive activity of Tregs on effector CD4 + T cells in retroviral infection is less well documented in vivo . We took advantage of a transgenic mouse in which Tregs can be selectively depleted to determine the influence of such cells on retrovirus-specific CD4 + T cell responses during an ongoing infection. Mice were infected with Friend retrovirus (FV), and Tregs were depleted during the acute phase of the infection. In nondepleted mice, activated CD4 + T cells produced Th1-type cytokines but did not exhibit any antiviral cytotoxicity as determined in a major histocompatibility complex (MHC) class II-restricted in vivo cytotoxic T lymphocyte (CTL) assay. Depletion of Tregs significantly increased the numbers of virus-specific CD4 + T cells and improved their cytokine production, whereas it induced only very little CD4 + T cell cytotoxicity. However, after dual depletion of Tregs and CD8 + T cells, conventional CD4 + T cells developed significant cytotoxic activity against FV epitope-labeled target cells in vivo and contributed to the control of virus replication. Thus, both Tregs and CD8 + T cells influence the cytotoxic activity of conventional CD4 + T cells during an acute retroviral infection.