| Summary: | The role of natural killer (NK) cells in the liver as first-line <i>post infectionem</i> (<i>p.i.</i>) effectors against blood-stage malaria and their responsiveness to protective vaccination is poorly understood. Here, we investigate the effect of vaccination on NK cell-associated genes induced in the liver by blood-stage malaria of <i>Plasmodium chabaudi.</i> Female Balb/c mice were vaccinated at weeks 3 and 1 before being infected with 10<sup>6</sup><i>P. chabaudi</i>-parasitized erythrocytes. Genes preferentially expressed by NK cells were investigated in livers of vaccination-protected and non-protected mice on days 0, 1, 4, 8, and 11 <i>p.i.</i> using microarrays, qRT-PCR, and chromosome landscape analysis. Blood-stage malaria induces expression of specific genes in the liver at different phases of infection, i.e., <i>Itga1</i> in expanding liver-resident NK (lrNK) cells, <i>Itga2</i> in immigrating conventional NK (cNK) cells; <i>Eomes</i> and <i>Tbx21</i> encoding transcription factors; <i>Ncr1, Tnfsf10, Prf1, Gzma, Gzmb, Gzmc, Gzmm,</i> and <i>Gzmk</i> encoding cytolytic effectors; natural killer gene complex (NKC)-localized genes encoding the NK cell receptors KLRG1, KLRK1, KLRAs1, 2, 5, 7, KLRD1, KLRC1, KLRC3, as well as the three receptors KLRB1A, KLRB1C, KLRB1F and their potential ligands CLEC2D and CLEC2I. Vaccination enhances this malaria-induced expression of genes, but impairs <i>Gzmm</i> expression, accelerates decline of <i>Tnfsf10</i> and <i>Clec2d</i> expression, whereas it accelerates increased expression of <i>Clec2i</i>, taking a very similar time course as that of genes encoding plasma membrane proteins of erythroblasts, whose malaria-induced extramedullary generation in the liver is known to be accelerated by vaccination. Collectively, vaccination reshapes the response of the liver NK cell compartment to blood-stage malaria. Particularly, the malaria-induced expansion of lrNK cells peaking on day 4 <i>p.i.</i> is highly significantly (<i>p</i> < 0.0001) reduced by enhanced immigration of peripheral cNK cells, and KLRB1F:CLEC2I interactions between NK cells and erythroid cells facilitate extramedullary erythroblastosis in the liver, thus critically contributing to vaccination-induced survival of otherwise lethal blood-stage malaria of <i>P. chabaudi</i>.
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