Abstract
During adaptive immune response, pathogen-specific CD8+ T cells recognize preferentially a small number of epitopes, a phenomenon known as immunodominance. Its biological implications during natural or vaccine-induced immune responses are still unclear. Earlier, we have shown that during experimental infection, the human intracellular pathogen Trypanosoma cruzi restricts the repertoire of CD8+ T cells generating strong immunodominance. We hypothesized that this phenomenon could be a mechanism used by the parasite to reduce the breath and magnitude of the immune response, favoring parasitism, and thus that artificially broadening the T cell repertoire could favor the host. Here, we confirmed our previous observation by showing that CD8+ T cells of H-2a infected mice recognized a single epitope of an immunodominant antigen of the trans-sialidase super-family. In sharp contrast, CD8+ T cells from mice immunized with recombinant genetic vaccines (plasmid DNA and adenovirus) expressing this same T. cruzi antigen recognized, in addition to the immunodominant epitope, two other subdominant epitopes. This unexpected observation allowed us to test the protective role of the immune response to subdominant epitopes. This was accomplished by genetic vaccination of mice with mutated genes that did not express a functional immunodominant epitope. We found that these mice developed immune responses directed solely to the subdominant/cryptic CD8 T cell epitopes and a significant degree of protective immunity against infection mediated by CD8+ T cells. We concluded that artificially broadening the T cell repertoire contributes to host resistance against infection, a finding that has implications for the host-parasite relationship and vaccine development.
Highlights
MHC class Ia-restricted CD8+ T cells are important mediators of the adaptive immune response against infections caused by intracellular microorganisms, including the digenetic intracellular protozoan parasite Trypanosoma cruzi, the causative agent of Chagas disease (American trypanosomiasis)
During experimental infection of H-2b or H-2a inbred mouse strains with parasites of the Y strain of T. cruzi, two epitopes were identified within the ASP-2 antigen represented by the VNHRFTLV or TEWETGQI peptides
We initially confirmed and extended our previous observation that experimental infection with the human intracellular pathogen T. cruzi restricted the repertoire of CD8+ T cells
Summary
MHC class Ia-restricted CD8+ T cells are important mediators of the adaptive immune response against infections caused by intracellular microorganisms, including the digenetic intracellular protozoan parasite Trypanosoma cruzi, the causative agent of Chagas disease (American trypanosomiasis). Recent studies on the CD8+ T-cell immune responses that occur during experimental T. cruzi infection in inbred mouse strains described a surprising immunodominance of certain epitopes expressed by members of a large family of T. cruzi surface antigens named trans-sialidases (TS) [1,5,12,13,14,15,16,17,18,19,20]. How and why this strong pattern of immunodominance is established is still a matter of debate. Immunodominance can emerge as a result of different mechanisms that regulate the formation of the complex of MHC-I-peptide on the surface of antigen presenting cells (APC) such as antigen concentration, stability or epitope availability after processing and translocation to the endoplasmic reticulum, where the MHC-I-peptide complex is assembled to be transported to the APC surface [21,22,23,24]
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