Immune regulation by natural killer cells through lysis of activated T cells (168.4)

Abstract

Abstract We have previously shown that natural killer (NK) cells can influence viral pathogenesis either by directly lysing virus-infected cells or through lysis of activated CD4 T cells. The latter phenomenon contributed to an inhibition of anti-viral T cells that favored viral persistence and host survival rather than lethal pathology during lymphocytic choriomeningitis virus (LCMV) infection. Infections with unrelated viruses, including Pichinde virus (PV), or inoculation with the type I IFN inducer, polyI:C, also triggered NK cell lysis of activated CD4 T cells. This lysis was coincident with poor control of PV infection and diminished PV-specific memory T cell responses, suggesting that such NK cell immunoregulation is a general principle of virus infection. LCMV infection was unable to induce NK cell lysis of activated T cells in IFN receptor (IFNAR)-deficient mice, implicating type I IFN in stimulation of this NK cell activity. Expression of the CD48, the ligand for the inhibitory NK cell receptor 2B4/CD244, was greater on NK cell-resistant CD8 T cells than their CD4 counterparts. However, genetic deletion of 2B4 facilitated lysis of activated CD8 T cells, and was associated with impaired clearance of both acute and chronic virus infections. Thus, type I IFN expression during virus infection or vaccination stimulates a 2B4/CD48-regulated, NK cell-mediated lysis of anti-viral T cells which impairs viral control and immune memory.