NK Cells Help To Induce CD8+-T-Cell Immunity againstToxoplasma gondiiin the Absence of CD4+T Cells

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.