The MHC-class II restricted immune response against parasitic proteinases: clearance-receptors as an alternative pathway for their endocytic uptake into antigen presenting cells

RESUMO

We have recently characterized the partial structure of a relatively dominant T cell epitope from the major T. cruzi cysteinyl proteinase (GP57/51 or cruzipain), and showed that it can trigger the secretion of gamma-interferon from CD4+ lymphocytes from chagasic patients. As generally observed for soluble antigens, T cell recognition of imunogenic peptides from cruzipain requires their prior uptake by antigen presenting cells (APC). Following endocytosis by the APC, cruzipain (a lysosomal proteinase by itself) has to unsergo intracellular degradation in acidic endosomes or lysosomes. The analysis of the fine specificity of cruzipain recognition by T lymphocytes (class II restricted responses) from chronic patients has implicated epitopes mapped to the catalytic domain of cruzipain rather than to its long COOH-terminal extension. Structural differences between these two domains may render them differentially susceptible to intracellular digestion in the APC. We now suggest that the functional inactivation of extracellular cruzipain by proteinase inhibitors available in tissue fluids may increase the efficieny of T cell responses. Recent data indicate that plasma inhibitor alpha2-macroglobulin M (alpha2M) can bind covalently to cruzipain, this being followed by APC uptake by means of the alpha2 macroglobulin receptor (alpha2MR) on monocytes. Similar clearance methanisms may allow highly efficient focusing, degradation and MHC-class II presentation of T cell stimulatory peptides from proteinases originating from allergens and other pathogenic parasites.