Epstein-Barr virus-induced gene 3 suppresses T helper type 1, type 17 and type 2 immune responses after Trypanosoma cruzi infection and inhibits parasite replication by interfering with alternative macrophage activation.

Abstract

The Epstein-Barr virus-induced gene 3 (EBI3) is a member of the interleukin-12 (IL)-12) family structurally related to the subunit p40 of IL-12 and forms a heterodimer either with the p28 subunit to build IL-27 or with p35 to form IL-35. Interleukin-27 is secreted by antigen-presenting cells whereas IL-35 appears to be produced mainly by regulatory T cells and regulatory B cells but both cytokines negatively regulate inflammatory immune responses. We here analysed the function of EBI3 during infection with the intracellular parasite Trypanosoma cruzi. Compared with C57BL/6 wild-type mice, EBI3-deficient (EBI3(-/-) ) mice showed a higher parasitaemia associated with an increased mortality rate. The EBI3(-/-) mice displayed an elevated inflammatory immune response with an increased production of T helper type 1 (Th1-), Th2- and Th17-derived cytokines. The increased Th2 immune response appears to have over-ridden the otherwise protective Th1 and Th17 immune responses by the induction of arginase-1-expressing alternatively activated macrophages in these mice. Hence, neutralization of IL-4 and arginase-1 activity partially restored protective immune responses in EBI3(-/-) mice. So far, our results demonstrate that EBI3 is an essential general regulator of inflammatory immune responses in experimental Chagas disease and is required for control of T.cruzi infection by inhibiting Th2-dependent alternative macrophage activation. Further studies are needed to dissect the underlying mechanisms and clarify whether EBI3 association with IL-27 or/and IL-35 accounts for its anti-inflammatory character in parasitic disease.