During microbial infection, host class I or class II molecules encoded by polymorphic MHC genes bind to antigenic peptides (T epitopes) produced by the invasor. Once associated with the appropriate MHC allele product, the peptide: MHC complex is targeted to the cell surface of the infected cell, where it is "presented" to naive or effector T cells. The intracellular pathways that generate small antigenic peptides by proteolytic processing and then enable MHC loading are collectively referred as antigen processing and presentation system. In the past years, the multiple checkpoints. That are targeted by pathogen-derived factors, viruses in particular, were characterized (Ploegh H 1999). In general terms, the viral products may target elements controlling (i) antigen-proteolysis by proteosomes, (ii) peptide transport to the ER (iii) MHC assembly and/or sorting and (iv) surface expression of class I MHC:peptide complexes.
The recent characterization of the specificity of killer T cells directed against T. cruzi should pave the way for elucidation of subversion tactics used by this pathogen. As shown in mice, the analysis of HLA-A2-restricted CTL specificities in the peripheral blood of chagasic patients has identified different members of a subfamily of TS-related antigens as targets: (Wizel et al. 1997, Low et al. 1997): two from amastigote-derived antigens, ASP-1 and ASP-2, and one trypomastigote-specific antigen, TSA-1. Teleologically, the usage of a vast array of polymorhic T. cruzi proteins as parent substrates for the proteosomal proteases makes sense because it should increase opportunities for epitope loading of the highly diverse MHC-class I products that exist in outbred populations. In other words, had the antigen structural variability involved exclusively monomorphic single genes, the parasite clones which display a variant sequence would tend to swarm most individuals from a genetically outbred population. Thus, structural variability imparted by multi-copy polymorphic genes may be advantageous to host-parasite equilibrium because it reduces the excessive risk associated with the growing diversification of parasite sub-populations. It is conceivable that some opportunistic T. cruzi clones may be able to subvert class I and/or class II presentation pathways. In a provocative study, Kahn and Wlekinski (1997) presented data suggesting that antigen variation of T. cruzi cell surface proteins can diminish the efficiency of anti-parasite T cell responses. It was suggested that the simultaneous expression of individual antigens from polymorphic TS subfamily may limit the availability of processed epitopes from each antigen below the threshold level required to stimulate a protective IFN-g response against the parasite. It will be interesting to know if similar mechanisms may allow for parasite escape from detection by class I-MHC restricted killer T cells. Admittedly, however, antigen-variation alone may not allow the parasites to escape from the antigen-presentation system of host cells from genetically outbred individuals (e.g. dogs and humans), because they count with a more diversified array of MHC allelic products. The parasite may need to use multiple mechanisms, possibly acting synergistically with antigen variation, to escape from immune detection during infection in humans.
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