Abstract
Conventional natural killer (cNK) cells, members of group 1 innate lymphoid cells, are a diverse cell subpopulation based on surface receptor expression, maturation, and functional potential. cNK cells are critical for early immunity to Toxoplasma gondii via IFNγ production. Acute cNK cell responses to infection with different strains of T. gondii have not yet been characterized in detail. Here, we comprehensively performed this analysis with Type I virulent RH, Type II avirulent ME49, and fully attenuated Type I cps1-1 strains. In response to these three parasite strains, murine cNK cells produce IFNγ and become cytotoxic and polyfunctional (IFNγ+CD107a+) at the site of infection. In contrast to virulent RH and avirulent ME49 T. gondii strains, attenuated cps1-1 induced only local cNK cell responses. Infections with RH and ME49 parasites significantly decreased cNK cell frequency and numbers in spleen 5 days post infection compared with cps1-1 parasites. cNK cell subsets expressing activating receptors Ly49H, Ly49D, and NKG2D and inhibitory receptors Ly49I and CD94/NKG2A were similar when compared between the strains and at 5 days post infection. cNK cells were not proliferating (Ki67−) 5 days post infection with any of the strains. cNK cell maturation as measured by CD27, CD11b, and KLRG1 was affected after infection with different parasite strains. RH and ME49 infection significantly reduced mature cNK cell frequency and increased immature cNK cell populations compared with cps1-1 infection. Interestingly, KLRG1 was highly expressed on immature cNK cells after RH infection. After RH and ME49 infections, CD69+ cNK cells in spleen were present at higher frequency than after cps1-1 infection, which may correlate with loss of the mature cNK cell population. Cytokine multiplex analysis indicated cNK cell responses correlated with peritoneal exudate cell, spleen, and serum proinflammatory cytokine levels, including IL-12. qPCR analysis of parasite-specific B1 gene revealed that parasite burdens may affect cNK cell responses. This study demonstrates infection with RH and ME49 parasites impacts cNK cell maturation during acute T. gondii infection. Different cNK cell responses could impact early immunity and susceptibility to these strains.
Highlights
Toxoplasma gondii is a highly prevalent food-borne obligate intracellular parasitic protozoan present in 30% of humans, which is a significant health concern as an opportunistic infection in immunocompromised people [1]
We tested whether Conventional natural killer (cNK) cell responses to acute T. gondii infection were different depending on parasite strain
Mice were infected with Type I highly virulent RH, attenuated RH strain cps1-1, and Type II strain avirulent ME49, and cNK cell frequencies and numbers were measured at the site of infection and spleen
Summary
Toxoplasma gondii is a highly prevalent food-borne obligate intracellular parasitic protozoan present in 30% of humans, which is a significant health concern as an opportunistic infection in immunocompromised people [1]. Conventional natural killer (cNK) cells are critical for innate immunity to T. gondii by producing IFNγ [5, 6]. CNK cells have been shown to have an important helper role in stimulating adaptive immunity to T. gondii. In CD4 T cell-deficient mice cNK cell IFNγ can help induce CD8 T cell immunity to T. gondii [7]. IFNγ produced by cNK cells promotes development of inflammatory dendritic cells, which, in turn, activates T cell responses [8]. CNK cells show cytotoxic activity in a response to T. gondii parasites and their subcellular components [9,10,11]. The importance of cNK cell cytotoxicity during T. gondii infection is still not known [12]
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