Journal
JOURNAL OF IMMUNOLOGY
Volume 184, Issue 11, Pages 6043-6052Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1000106
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Funding
- United Kingdom Medical Research Council [GO 400225, G0500563]
- Wellcome Trust
- MRC [G0400225, G0500563] Funding Source: UKRI
- Medical Research Council [G0500563, G0400225] Funding Source: researchfish
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Rapid cell-mediated immune responses, characterized by production of proinflammatory cytokines, such as IFN-gamma, can inhibit intraerythrocytic replication of malaria parasites and thereby prevent onset of clinical malaria. In this study, we have characterized the kinetics and cellular sources of the very early IFN-gamma response to Plasmodium falciparum-infected RBCs among human PBMCs. We find that NK cells dominate the early (12-18 h) IFN-gamma response, that NK cells and T cells contribute equally to the response at 24 h, and that T cells increasingly dominate the response from 48 h onward. We also find that although gamma delta T cells can produce IFN-gamma in response to P. falciparum-infected RBCs, they are greatly outnumbered by alpha beta T cells, and thus, the majority of the IFN-gamma(+) T cells are alpha beta T cells and not gamma delta T cells; gamma delta T cells are, however, an important source of TNF. We have previously shown that NK cell responses to P. falciparum-infected RBCs require cytokine and contact-dependent signals from myeloid accessory cells. In this study, we demonstrate that NK cell IFN-gamma responses to P. falciparum-infected RBCs are also crucially dependent on IL-2 secreted by CD4(+) T cells in an MHC class II-dependent manner, indicating that the innate response to infection actually relies upon complex interactions between NK cells, T cells, and accessory cells. We conclude that activation of NK cells may be a critical function of IL-2-secreting CD4(+) T cells and that standard protocols for evaluation of Ag-specific immune responses need to be adapted to include assessment of NK cell activation as well as T cell-derived IL-2. The Journal of Immunology, 2010, 184: 6043-6052.
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