Since the amastigote division proceeds asynchronously (Dvorak & Hyde 1973), the amastigotes which succeed at subverting the class I antigen presentation pathway should gradually transform into trypomastigotes. The trypomastigote specific CTL may then attack the target cells as soon as the epitopes (derived from TS-related or other dominant antigens) generated in the cytossol reach the threshold required for class I MHC presentation. Although the rates of MHC-loading and surface expression may vary from one cell to another, it is reasonable to predict that the target cells still harbors some intracellular amastigotes at the time of attack by the trypomastigote-specific killer T cells. This time-course make sense because the antigen presentation machinary should not be anymore functional at the very late stage of pseudocyst formation. We may therefore deduce that host cell killing at a relatively early stages of trypomastigote production is a suitable compromise with the host, because in this case, the release of just a few trypomastigotes should suffice to ensure long term survival of both host and parasites. As a corollary, we may predict that the extent to which tissues are exposed to prematurely released amastigotes is variable, and dependent on the interplay between interactions involving class I MHC-allelles (host genetic) and the highly diverse surface antigens from T. cruzi. (parasite genetic make up). This fundamental tenet, leads to the following testable assertions: (1) killer T cells which recognize amastigote epitopes are the most effective effectors of class I MHC-protective immune responses (this assertion has obvious implications for vaccine design); (2) amastigote clones can suceed at subverting the class I pathway of antigen presentation exist, but the phenotype is linked to host MHC-haplotype; (3) expression of the pathogenic phenotype deoends on the activity of CD8+ killers which recognize trypomastigote specific epitopes (TS-related antigens?) at a later stage of intracellular development (implications for vaccine design).
We postulate that the deposition of high numbers of nonmotile amastigotes in tissues may be crucial for the onset of apoptosis of effector cells from the Th1 subset (and Tc1). In addition, the amastigotes may also induce non-specific supression by stimulating cells (Th2 or Tc2) to produce TGF-b or IL10 in the inflamed tissues. In summary, we propose that trypomastigote-specific killer cells may play a multiple role in Chagas disease: they are critically important for protection, they may indirectly contribute to Th2-down regulation (to discussed below), and may be promote immunopathology by inducing the premature release of pro-inflammatory amastigotes in adjacent tissues.
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