NOD2-RIP2-Mediated Signaling Helps Shape Adaptive Immunity in Visceral Leishmaniasis.

Interferon γ (IFN-γ) and interleukin 17A (IL-17A)-producing cells are described to be related to the protection against Leishmania infantum infection. How the immune system coordinates the balance between T-helper type 1 (Th1) and 17 (Th17) responses during visceral leishmaniasis (VL) is still unknown. Here, we combined transcriptional profiling, using RNA sequencing analysis of human samples, with an experimental model to show that Th17-related genes are suppressed and that Th1 signature genes are induced during human VL. The high amount of Th1 cells in VL was dependent on the NOD2-RIP2 signaling in dendritic cells, which was crucial for interleukin 12 production through the phosphorylation of MAPK. On the other hand, this pathway inhibits Th17 cells by limiting interleukin 23 production. As a consequence, Nod2-/- and Rip2-/- mice showed defects in Th1 responses and higher parasite loads as compared to WT mice. Together, the data demonstrate that the NOD2-RIP2 pathway is activated in murine and human VL and plays a role in shaping adaptive immunity toward a Th1 profile.

Cytokine-activated NK cells inhibit PMN apoptosis and preserve their functional capacity.

Natural killer (NK) cells and polymorphonuclear cells (PMNs) play a critical role in the first line of defense against microorganisms. Upon host infection, PMNs phagocytose invading pathogens with subsequent killing by oxidative or nonoxidative mechanisms. NK cells are known to have immunoregulatory effects on T cells, B cells, dendritic cells (DCs), and monocytes through secretion of various soluble products and cell-cell contact. However, their impact on PMN survival and function is not well known. We found that soluble factors derived from cytokine-activated NK cells delay PMN apoptosis and preserve their ability to perform phagocytosis and produce reactive oxygen species (ROS). The expression patterns of CD11b and CD62L on PMNs differed according to the cytokine combination used for NK-cell stimulation. Irrespective of the NK-cell treatment, however, PMN survival was prolonged with sustained functional capacity. We found that interferon gamma, granulocyte-macrophage colony-stimulating factor, and tumor necrosis factor alpha produced by NK cells upon stimulation with cytokines played a crucial role in NK cell-mediated effects on PMNs. Our study demonstrates that soluble factors derived from cytokine-activated NK cells send survival signals to PMNs, which would promote their accumulation and function at the site of inflammation in vivo.

Fcgamma receptor-mediated antigen uptake by lung DC contributes to allergic airway hyper-responsiveness and inflammation.

During asthma, lung DC capture and process antigens to initiate and maintain allergic Th2 cell responses to inhaled allergens. The aim of the study was to investigate whether allergen-specific IgG, generated during sensitization, can potentiate the acute airway inflammation through Fcgamma receptor (FcgammaR)-mediated antigen uptake and enhance antigen presentation resulting in augmented T-cell proliferation. We examined the impact of antigen presentation and T-cell stimulation on allergic airway hyperresponsiveness and inflammation using transgenic and gene-deficient mice. Both airway inflammation and eosinophilia in bronchoalveolar lavage fluid were markedly reduced in sensitized and challenged FcgammaR-deficient mice. Lung DC of WT, but not FcgammaR-deficient mice, induced increased antigen-specific CD4+ T-cell proliferation when pulsed with anti-OVA IgG immune complexes. Intranasal application of anti-OVA IgG immune complexes resulted in enhanced airway inflammation, eosinophilia and Th2 cytokine release, mediated through enhanced antigen-specific T-cell proliferation in vivo. Finally, antigen-specific IgG in the serum of sensitized mice led to a significant increase of antigen-specific CD4+ T-cell proliferation induced by WT, but not FcgammaR-deficient, lung DC. We conclude that FcgammaR-mediated enhanced antigen presentation and T-cell stimulation by lung DC has a significant impact on inflammatory responses following allergen challenge in asthma.