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Modulation of immune responses by macrophages

“Classically” IFN-Y-activated “M1” macrophages produce IL-12 which drives type 1 immune responses. In the presence of IL-10, glucocorticoids or apoptotic cells, macrophages are “alternatively” activated (“M2”),74 producing mainly IL-10 and TGF-(3 which antagonize the protective action of IFN-y.

IL-12 plays a crucial role in resistance to T. cruzi infection75 due to its ability to promote IFN-y and TNF-a-dependent NO production.76 IL-18 may contribute to trigger IFN-y.77 Its early production, combined with IL-12, improves resistance to infection.52

IL-27 is involved in protection78 by favoring Th1-dependent control of parasite multiplication and limiting Th2 responses and alternative macrophage activation. It has also a beneficial effect for the host by controlling excessive production of pro-inflammatory cytokines, like IL-6 and TNF-a, known to be involved in mortality when released at high levels during acute infection.79

IL-10 limits the potential harmful effects of excessive inflammatory cytokines.46 When produced in higher quantities by M2 macrophages, it prevents the activating action of IFN-y. IL-10 also regulates the interplay between macrophages and NK cells.25 The balance between IFN-y and IL-10 expression is crucial in modulating the resistance or susceptibility to T. cruzi infection and depends on the host genetic background: cruzipain favors M2 macrophage activation in Balb/c mice,80 while in C57BL/6 mice it generates a predominant Th1 response.81

Other immunosuppressive or anti-inflammatory mediators like TGF-(3 and PGE2 are produced during the acute phase of infection.82,83 Interestingly, the parasite activates this cytokine to invade cells bearing TGF-(3 receptors while TGF-(3 limits IFN-Y-activation of macrophages.84,85 On the other hand, PGE2 limits the production of IFN-y and TNF-a83 known to have harmful effects when present at too high levels,86,79 while preserving the NO-dependent trypanocidal action. Yet it exerts a detrimental effect by inhibiting lymphocyte proliferation and IL-2 production.87

Macrophages as antigen-presenting cells

T. cruzi macrophage infection impairs Ag presentation to CD41 T cells, leading to a reduced proliferation.88 This is related to impeded ability to take up and catabo- lize exogenous antigen, decreased expression of MHC class II molecules, and/or defective adhesion to T cells (see Section 4.1), but likely not to deficient delivery of co-stimulatory signals.88,89

On the contrary, T. cruzi does not inhibit MHC class I Ag presentation to CD81 T cells.90 However, MHC I-dependent Ag presentation may take time to become efficient, through a delay in immunoproteasome synthesis, as well as in MHC class I mRNA synthesis and cell surface expression.91 Such delay results from transient inhibition by the parasite of protein tyrosine phosphatase in macrophage. Thus, in the first hours after invasion, the parasite could delay early CTL-mediated immunity long enough to facilitate parasite establishment inside the host.91

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