Subdominant/Cryptic CD8 T Cell Epitopes Contribute to Resistance against Experimental Infection with a Human Protozoan Parasite

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.

Adenovirus Vector-Induced CD8+ T Effector Memory Cell Differentiation and Recirculation, But Not Proliferation, Are Important for Protective Immunity Against Experimental Trypanosoma cruzi Infection

“…Frequencies, phenotypes, and functions of specific CD8 + T cells in vaccinated mice after infectious challenge with T. cruzi Protective immunity against T. cruzi infection can be achieved by genetic vaccination with the ASP-2 gene following a heterologous plasmid DNA priming-recombinant adenovirus boosting regimen (De Alencar et al, 2009;Haolla et al, 2009;Dominguez et al, 2011Dominguez et al, , 2012Rigato et al, 2011). In C57BL/6 mice, protective immunity is mediated by CD8 + T cells that are specific for the immunodominant epitope VNHRFTLV (De Alencar et al, 2009;Rigato et al, 2011).…”

“…Within the past few years, we reported that the heterologous prime-boost strategy successfully vaccinates highly susceptible A/Sn mice against systemic infection with the human intracellular protozoan parasite Trypanosoma cruzi, the causative agent of Chagas disease (American trypanosomiasis) (De Alencar et al, 2009;Haolla et al, 2009;Dominguez et al, 2011Dominguez et al, , 2012Rigato et al, 2011). In these experiments, we used a recombinant plasmid DNA for priming and the human replication-defective recombinant adenovirus type 5 for boosting, both expressing the amastigote surface protein-2 (ASP-2) of T. cruzi.…”

Long-Term Immunity to Trypanosoma cruzi in the Absence of Immunodominanttrans-Sialidase-Specific CD8+T Cells

“…ϩ T cells could limit the generation of potentially more effective parasite-focused responses capable of complete parasite eradication (21,27,62). If immunodomination by TSKB20-and TSKB18-specific CD8 ϩ T cells inhibits development of other potentially more protective CD8 ϩ responses, one would predict that TSKB20/TSKB18 Tg mice should exhibit better long-term control of T. cruzi than their WT counterparts.…”

“…Development of T cell-based vaccines has focused on enhancing immunodominant T cells prior to pathogen encounter, though boosting subdominant or cryptic responses has also been suggested as an important goal for vaccines (62,64). Induction of broadly focused T cell responses might be particularly important for therapeutic vaccines that enhance control of chronically infecting pathogens for which the immunodominant response has already proven ineffective at establishing an immunological cure.…”

Therapeutic Vaccination against the Rhesus Lymphocryptovirus EBNA-1 Homologue, rhEBNA-1, Elicits T Cell Responses to Novel Epitopes in Rhesus Macaques

“…Enhancing immune responses to subdominant antigens can confer some degree of protection against several infections (45)(46)(47)(48)(49). Pathogens like EBV restrict host T cell responses during infection, facilitating pathogen replication and/or persistence by avoiding broader immune responses.…”