NK Cells Help To Induce CD8 + -T-Cell Immunity against Toxoplasma gondii in the Absence of CD4 + T Cells

Abstract

ABSTRACT CD8 + T-cell immunity plays an important role in protection against intracellular infections. Earlier studies have shown that CD4 + T-cell help was needed for launching in vivo CD8 + T-cell activity against these pathogens and tumors. However, recently CD4 + T-cell-independent CD8 responses during several microbial infections including those with Toxoplasma gondii have been described, although the mechanism is not understood. We now demonstrate that, in the absence of CD4 + T cells, T. gondii -infected mice exhibit an extended NK cell response, which is mediated by continued interleukin-12 (IL-12) secretion. This prolonged NK cell response is critical for priming parasite-specific CD8 + T-cell immunity. Depletion of NK cells inhibited the generation of CD8 + T-cell immunity in CD4 −/− mice. Similarly neutralization of IL-12 reduces NK cell numbers in infected animals and leads to the down-regulation of CD8 + T-cell immunity against T. gondii . Adoptive transfer of NK cells into the IL-12-depleted animals restored their CD8 + T-cell immune response, and animals exhibited reduced mortality. NK cell gamma interferon was essential for cytotoxic T-lymphocyte priming. Our studies for the first time demonstrate that, in the absence of CD4 + T cells, NK cells can play an important role in induction of primary CD8 + T-cell immunity against an intracellular infection. These observations have therapeutic implications for immunocompromised individuals, including those with human immunodeficiency virus infection.