Monocytes Play an IL-12-Dependent Crucial Role in Driving Cord Blood NK Cells to Produce IFN-g in Response to Trypanosoma cruzi

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.

Congenital Chagas disease as an ecological model of interactions between Trypanosoma cruzi parasites, pregnant women, placenta and fetuses

“…Twarting such limitation requires an activation of fetal/neonatal monocytes and DCs. Monocytes produce IL-12 that synergizes with IL-15 to activate in turn NK cells and particularly the CD56 bright NK cell subpopulation releasing IFN-␥ (Guilmot et al, 2013(Guilmot et al, , 2014. DCs trigger T cell proliferation (preferentially CD8+ T cells) and more IFN-␥ release (Rodriguez et al, 2012a,b).…”

Protection and pathology during parasite infection: IL‐10 strikes the balance

“…Activation of both the influx of cells arriving in the infected tissue and the macrophages and DCs resident there, results in copious production of inflammatory cytokines, including IL-12, TNFa and TNF-family molecules (55)(56)(57)(58)(59). Recruited NK cells respond to IL-12 by releasing Interferon-c (IFNc) (60)(61)(62), which is also released early in the immune response by NKT cells (63-65) and neutrophils (66). IFNc signalling feeds back to the local and recruited macrophages and enhances their cytokine production and parasite killing (59,67,68).…”

Critical roles of conventional dendritic cells in promoting T cell-dependent hepatitis through regulating natural killer T cells

“…One of the essential functions of IL‐12 is inducing IFN‐γ production by a few cell types, including CD4 + T cells, NK and T cells . We wished to determine the source of IFN‐γ induced by IL‐12 in the ConA‐induced hepatitis model.…”

“…One of the essential functions of IL-12 is inducing IFNg production by a few cell types, including CD4 1 T cells, NK and T cells [22,41,42]. We wished to determine the ability of NKT cells to produce IFN-g after concanavalin A (ConA) treatment was abolished in CD11c-diphtheria toxin receptor transgenic (DTR Tg) mice, which can be restored by IL-12 reconstitution.…”