CD8+ T-Cell Responses to Trypanosoma cruzi Are Highly Focused on Strain-Variant trans-Sialidase Epitopes

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Abstract
CD8+ T cells are crucial for control of a number of medically important protozoan parasites, including Trypanosoma cruzi, the agent of human Chagas disease. Yet, in contrast to the wealth of information from viral and bacterial infections, little is known about the antigen specificity or the general development of effector and memory T-cell responses in hosts infected with protozoans. In this study we report on a wide-scale screen for the dominant parasite peptides recognized by CD8+ T cells in T. cruzi–infected mice and humans. This analysis demonstrates that in both hosts the CD8+ T-cell response is highly focused on epitopes encoded by members of the large trans-sialidase family of genes. Responses to a restricted set of immunodominant peptides were especially pronounced in T. cruzi–infected mice, with more than 30% of the CD8+ T-cell response at the peak of infection specific for two major groups of trans-sialidase peptides. Experimental models also demonstrated that the dominance patterns vary depending on the infective strain of T. cruzi, suggesting that immune evasion may be occurring at a population rather than single-parasite level. The authors of this paper conducted a broad screen to identify the major proteins in Trypanosoma cruzi, the causative agent of Chagas disease, that allow for detection and control of this intracellular pathogen by CD8+ T cells. This study is the first to show that a complex pathogen such as T. cruzi elicits a T-cell response focused on a few peptides, despite having a genome of >12,000 genes capable of encoding hundreds of thousands of potential target epitopes. The immunodominant CD8+ T-cell targets in both murine and human T. cruzi infection are almost exclusively peptides within multiple trans-sialidase proteins that are encoded by the large and diverse trans-sialidase gene family. trans-sialidase genes show great potential for variation, and the frequency of individual trans-sialidase epitopes appears to vary significantly in different parasite strains, giving rise to distinct patterns of T-cell responses to different T. cruzi isolates. The authors hypothesize that the massive expansion of this gene family under immunological pressure and the resulting variable expression of specific T-cell epitopes provides a mechanism of immune escape for T. cruzi.