Apoptotic lymphocytes treated with IgG from Trypanosoma cruzi infection increase TNF‐α secretion and reduce parasite replication in macrophages

Abstract

Phagocytic removal of apoptotic lymphocytes exacerbates replication of Trypanosoma cruzi in macrophages. We investigated the presence of Ab against apoptotic lymphocytes in T. cruzi infection and the role of these Ab in parasite replication. Both control and chagasic serum contained IgG Ab that opsonized apoptotic lymphocytes. Treatment of apoptotic lymphocytes with purified IgG from chagasic, but not control serum, reduced T. cruzi replication in macrophages. The protective effect of chagasic IgG depended on Fcc receptors, as demonstrated by the requirement for the intact Fc portion of IgG, and the effect could be abrogated by treating macrophages with an anti-CD16/CD32 Fab fragment. Chagasic IgG displayed increased reactivity against a subset of apoptotic cell Ag, as measured by flow cytometry and immunoblot analyses. Apoptotic lymphocytes treated with chagasic IgG, but not control IgG, increased production of TNF-a, while decreasing production of TGF-b1 by infected macrophages. Increased control of parasite replication required TNF-a production. Previous immunization with apoptotic cells or injection of apoptotic cells opsonized with chagasic IgG reduced parasitemia in infected mice. These results indicate that Ab raised against apoptotic cells could play a protective role in control of T. cruzi replication by macrophages.Key words: Ab . Apoptosis . Fc receptors . Phagocytosis . Trypanosoma cruzi IntroductionInfection with Trypanosoma cruzi, the causative agent of Chagas' disease, induces Ab against both parasite Ag [1-4] and self molecules [5][6][7]. Ab play a protective role in T. cruzi infection [1][2][3][4][5]7], but the mechanisms involved are not completely understood.Infection with T. cruzi induces lymphocyte apoptosis [8][9][10][11][12], and the phagocytic clearance of apoptotic lymphocytes drives replication of T. cruzi in macrophages [13]. Parasite replication results from a biochemical cascade that originates from binding of apoptotic cells à These authors contributed equally to this work. Eur. J. Immunol. 2010. 40: 417-425 DOI 10.1002 Immunity to infection 417 to a V b 3 integrin, followed by production of PGE 2 and TGF-b1, induction of ornithine decarboxylase and increased production of the polyamine putrescine [13]. T. cruzi is unable to synthesize putrescine and depends on uptake of exogenous putrescine for intracellular growth [14]. Phagocytosis of apoptotic cells induces production of TGF-b1, but not proinflammatory cytokines [15]. However, phagocytosis of apoptotic cells is enhanced by serum opsonins, including Ab [16], and Ab to apoptotic cells can lead to secretion of proinflammatory cytokines [15,17].Immunization with apoptotic cells induces production of autoantibodies [18]. However, it is unclear whether such autoantibodies play an immunoregulatory role. In the present study, we sought to determine whether infection with T. cruzi elicited production of Ab against apoptotic lymphocytes. We found that apoptotic lymphocytes treated with chagasic IgG induced a proinflammatory cytokine resp...

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