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Abstract
We previously reported that foetuses congenitally infected with Trypanosoma cruzi, the agent of Chagas disease, mount an adult-like parasite-specific CD8+ T-cell response, producing IFN-g, and present an altered NK cell phenotype, possibly reflecting a post-activation state supported by the ability of the parasite to trigger IFN-g synthesis by NK cells in vitro. We here extended our knowledge on NK cell activation by the parasite. We compared the ability of T. cruzi to activate cord blood and adult NK cells from healthy individuals. Twenty-four hours co-culture of cord blood mononuclear cells with T. cruzi trypomastigotes and IL-15 induced high accumulation of IFN-g transcripts and IFN-g release. TNF-a, but not IL-10, was also produced. This was associated with up-regulation of CD69 and CD54, and down-regulation of CD62L on NK cells. The CD56bright NK cell subset was the major IFN-g responding subset (up to 70% IFN-g-positive cells), while CD56dim NK cells produced IFN-g to a lesser extent. The response points to a synergy between parasites and IL-15. The neonatal response, observed in all newborns, remained however slightly inferior to that of adults. Activation of IL-15-sensitized cord blood NK cells by the parasite required contacts with live/intact parasites. In addition, it depended on the engagement of TLR-2 and 4 and involved IL-12 and cross-talk with monocytes but not with myeloid dendritic cells, as shown by the use of neutralizing antibodies and cell depletion. This work highlights the ability of T. cruzi to trigger a robust IFN-g response by IL-15-sensitized human neonatal NK cells and the important role of monocytes in it, which might perhaps partially compensate for the neonatal defects of DCs. It suggests that monocyte- and IL-12- dependent IFN-g release by NK cells is a potentially important innate immune response pathway allowing T. cruzi to favour a type 1 immune response in neonates.
Highlights
Chagas disease, caused by the protozoa Trypanosoma cruzi, is a major cause of cardiac failure in Latin America where it infects 8– 10 million people [1]
We show that Trypanosoma cruzi, the protozoa agent of Chagas disease, rapidly and strongly up-regulates the production of IFN-g by IL-15-primed cord blood NK cells to a level close to that produced by adult NK cells
CBMC co-cultured for 24 h with T. cruzi live trypomastigotes associated with IL-15 (20 ng/mL) produced large amounts of IFN-g, low levels of TNF-a and no IL10 in response to T. cruzi associated with IL-15, whereas parasites or IL-15 alone were markedly less effective, suggesting they synergize to trigger the release of these cytokines (Table 1)
Summary
Chagas disease, caused by the protozoa Trypanosoma cruzi, is a major cause of cardiac failure in Latin America where it infects 8– 10 million people [1]. Neonates congenitally-infected with T. cruzi mount a mature parasitespecific CD8+ T lymphocyte response producing IFN-g [2], whereas uninfected infants from T. cruzi-infected mothers (probably by receiving circulating parasite molecules from their mothers) display a pro-inflammatory environment associated with activated monocytes [3]. Both congenitally infected and uninfected infants from chagasic mothers develop boosted type 1 immune responses to vaccines routinely administered in early life [4]. These data point out the ability of T. cruzi to overcome the immune deficiency associated with early life [5,6]
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