Human T cell responses against the major cysteine proteinase (cruzipain) of Trypanosoma cruzi: Role of the multifunctional alpha sub(2)-macroglobulin receptor in antigen presentation by monocytes

• Published in: International immunology Vol. 9; no. 6; pp. 825 - 834
• Main Authors: Morrot, A, Strickland, D K, De Lourdes Higuchi, M, Reis, M, Pedrosa, R, Scharfstein, J
• Format: Journal Article
• Language: English
• Published: 01.06.1997
• Subjects: Trypanosoma cruzi
• ISSN: 0953-8178

Chagas' disease patients (CDP) develop both humoral and cellular immune responses against the major cysteine proteinase (cruzipain) from Trypanosoma cruzi. Here we demonstrate that complexes formed by cruzipain and alpha sub(2)-macroglobulin ( alpha sub(2)M) are efficiently internalized by human monocytes, and that this process results in enhanced presentation of cruzipain peptides to CD4 super(+) T cells from CDP. Purified or serum alpha sub(2)M binds to polymorphic cruzipains, but only a fraction of the proteinases become covalently linked. Once bound to alpha sub(2)M, fluorescein-labeled cruzipain (FITC-cruzipain) or [ super(125)I]cruzipain were more efficiently internalized by normal peripheral blood mononuclear cells (PBMC) or monocytes; this effect was abolished by (i) pre-treating the cells with receptor-associated protein (rRAP), a known antagonist the of alpha sub(2)M receptor ( alpha sub(2)MR/LRP), and (ii) inactivating [ super(125)I]cruzipain's active site prior to the reaction with alpha sub(2)M, indicating that the exposure of receptor binding sites on alpha sub(2)M complexes required bait region cleavage. We then sought to determine if the alpha sub(2)MR/LRP-dependent uptake of alpha sub(2)M:cruzipain by monocytes resulted in increased CD4 super(+) T cell responses of PBMC-CDP (n = 13). These effects were only revealed after depletion of CD19 super(+) B lymphocytes from PBMC-CDP; the threshold of T cell stimulation was far lower in cultures stimulated with alpha sub(2)M:cruzipain, as compared to antigen alone. Myocardial specimens from CDP with chronic myocardiopathy (three necropsies) were analyzed by immunohistochemistry with mAb anti-cruzipain or anti- alpha sub(2)MR/LRP (CD91 super(+)). Extracellular depots of cruzipain were localized amidst inflammatory mononuclear infiltrates, part of which contained CD91 super(+) macrophage-like cells. Ongoing studies should clarify if T. cruzi cysteinyl proteinases play a role in the pathogenesis of Chagas' heart disease.