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Biology Articles » Parasitology » A Role for Extracellular Amastigotes in the Immunopathology of Chagas Disease » Abortive cycles of amastigote replication: role of class I MHC killer T cells

Abortive cycles of amastigote replication: role of class I MHC killer T cells
- A Role for Extracellular Amastigotes in the Immunopathology of Chagas Disease


On a first impression, the ability of CTL to kill non-phagocytic targets which harbor intracellular trypomastigotes would seem to be a redundant process, because most of the infective parasites should be anyway released into the extracellular fluids upon host cell burst. However, target cell death by apoptosis should be advantageous to the host (Andrade et al. 1999), inasmuch as this mechanism would spare host tissues from the detrimental effects of necrosis that would otherwise occur if the target cells collapse due to excessive numbers of parasites. Since mutual destruction is not a fruitful evolutionary strategy, it is unlikely that host cell apoptosis also destroys all the intracellular parasites. Once released to extracellular spaces, the trypomastigotes tend to move away from the primary foci of infection, while the non-motile extracellular amastigotes [which resist C' mediated lysis (Iida et al. 1989) tend to accumulate in the proximity of the primary site of infection (Fig. 1) . Of necessity, there is only one obvious pathway that may permit the survival of these extracellular amastigotes: the maintenance of a supressive environment, determined by TGF-b or IL10, or alternative mediators. If spared from death, the amastigote may leave the parasitophorous vacuole and lodge in the cytosol, where they actively proliferate (Ley et al. 1988). As previously discussed, we postulate that some amastigote clones may succeed in subverting the class I MHC presentation pathway. Hence, the killing of target cells by CTL (TC2) specific for trypomastigote peptides may release a substantial number of amastigotes into the interstitium. New cycles of abortive replication may ensue, once other macrophages are recruited and likewise infected. In short, our model (Fig. 1) predicts that the ultimate fate (death or replication) of the intracellular amastigotes lodged in the macrophages should be determined by the local balance between cytokines released by activated Th1 (eg. IFN-g, TNF-a) or Th2 (TGF-b or IL10) or by equivalent cytokines released by Tc1/Tc2 CD8+ lymphocytes. As discussed earlier in this text, macrophage stimulation by parasite-factors that induce PGE2 may down-regulate the pro-inflammatory response induced by t-GPI-mucins (Procopio et al. 1999).

In the acute infection, the tissue parasite load in non-phagocytic cells from lymphoid organs, such as the spleen, is initially high but decreases when cellular immune effectors intervene. It is possible that the extracellular amastigotes released from host cells may somehow contribute to the massive polyclonal activation of lymphocytes (D'Imperio-Lima et al. 1985) and/or for the transient state of non-specific immunosuppression (Teixeira et al. 1978) observed. As already mentioned, there is a close temporal relationship between the drop in tissue parasite load and the onset of these immunoregulatory changes in peripheral lymphoid tissues (Dos Reis 1997). Given the evidences that the activity of CD8+ CTL effectors is critically involved in the parasite clearance from non-phagocytic cells in various tissues, perhaps the killer T cells may indirectly play a role in the aforementioned regulatory abnormalities. As already discussed (Fig. 1, left panel), target cell death by trypomastigote-specific CTL may lead to the premature release of some intracellular amastigotes and/or trypomastigotes in the interstitium. Consistent with predictions from the our model, Caulada-Benedetti et al. (1998) have recently reported that macrophages exposed to live amastigotes activate both lymph node and spleen CD4+ and CD8+ T cells. By extension, we suggest that the pool of spleen CD4+ T cells which undergo activation-induced cell death (AICD) upon in vitro stimulation with anti-CD3 (Dos Reis et al. 1995) may be enriched with amastigote-specific CD4+ T cells. As argued by these authors, the elimination of activated Th1-type cells by PCD may favor the polarization of Th2-type responses at late stages of the acute infection (Dos Reis 1997). Perhaps amastigote-derived antigens can exponentially build up in lymphoid tissues due to successive rounds of abortive infection induced by trypomastigote-specific killer T cells (Tc2). If true, CD8 cells from this subset should indirectly control the induction of anergy, clonal deletion and/or Th2-dependent down-regulation of amastigote-specific CD4+ Th1 lymphocytes. As a corollary, we may predict that individual animals or patients which exhibit deficits in trypomastigote-specific CTL (Tc2) should not be able to release substantial numbers of intracellular amastigotes to lymphoid tissues. As a result of such deficits, amastigote-specific CD4+ Th1 cells would not be as efficiently eliminated or down-regulated, perhaps allowing for the expansion of the Th1 inflammatory subset, thereby aggravating acute and chronic immunopathology. These general predictions are consistent with data suggesting that early immunological events can influence the development of inflammation at chronic stages of infection (Mariano et al. 1999). Perhaps the mechanistic hypothesis outlined here (Fig. 1, lef panel) may offers a framework to study the mechanisms underlying the contrasting behavior of the Colom-biana-Balb/C model of chronic carditis (Ribeiro dos Santos et al. 1992). Instead of the CD8+ T cells (anti-parasite) which dominate the chronic myocardial infiltrates in the majority of mice models (Tarleton et al. 1997) and in human as well (Reis et al. 1997) the infection of Balb/C mice with Colombiana favors the induction of autoreactive CD4 T cell effectors which attack cardiac tissues. According to the tenets of our model, the Balb/C animals infected by the Colombiana strain may have failed to efficiently eliminate or down-regulate cross-reactive amastigote-specific Th1 CD4 cells in lymphoid tissues, perhaps due to a primary deficit in the function of trypomastigote-specific CD8 T cells (Tc2). It will be interesting to know if the putative self-epitopes recognized by these CD4 T cell clones are structurally homologous to amastigote antigens from the Colombiana strain.

Of course, other regulatory pathways may be of course involved in the Th1/Th2 polarization observed in chagasic infection. For example, it has been recently proposed that the conversion of Tc1 into Tc2 suppressors depends on the NO releasing activity of macrophages, which is in turn stimulated by Th1 lymphocytes. It is believed that the cytokine profile of Tc2 may ensure that target cell apoptosis proceeds without the characteristic necrosis and tissue injury associated with the activity of CTL from the Tc1 subset (Kolb & Kolb-Bachofen 1998). In a recent study of PBMC responses, Bahia-Oliveira et al. (1998) observed that type 2-cytokines predominate in the indeterminate stage of the human disease, while type 1 cytokines are more frequently observed in symptomatic individuals. It will be important to know if Tc2 and Tc1 contribute to these fluctuations, and assess their relationship to the distribution of cellular infiltrates in the myocardial tissues (Higuschi et al. 1993).

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