Costimulatory Effects of an Immunodominant Parasite Antigen Paradoxically Prevent Induction of Optimal CD8 T Cell Protective Immunity

Abstract

Trypanosoma cruzi infection is controlled but not eliminated by host immunity. The T. cruzi trans-sialidase (TS) gene superfamily encodes immunodominant protective antigens, but expression of altered peptide ligands by different TS genes has been hypothesized to promote immunoevasion. We molecularly defined TS epitopes to determine their importance for protection versus parasite persistence. Peptide-pulsed dendritic cell vaccination experiments demonstrated that one pair of immunodominant CD4+ and CD8+ TS peptides alone can induce protective immunity (100% survival post-lethal parasite challenge). TS DNA vaccines have been shown by us (and others) to protect BALB/c mice against T. cruzi challenge. We generated a new TS vaccine in which the immunodominant TS CD8+ epitope MHC anchoring positions were mutated, rendering the mutant TS vaccine incapable of inducing immunity to the immunodominant CD8 epitope. Immunization of mice with wild type (WT) and mutant TS vaccines demonstrated that vaccines encoding enzymatically active protein and the immunodominant CD8+ T cell epitope enhance subdominant pathogen-specific CD8+ T cell responses. More specifically, CD8+ T cells from WT TS DNA vaccinated mice were responsive to 14 predicted CD8+ TS epitopes, while T cells from mutant TS DNA vaccinated mice were responsive to just one of these 14 predicted TS epitopes. Molecular and structural biology studies revealed that this novel costimulatory mechanism involves CD45 signaling triggered by enzymatically active TS. This enhancing effect on subdominant T cells negatively regulates protective immunity. Using peptide-pulsed DC vaccination experiments, we have shown that vaccines inducing both immunodominant and subdominant epitope responses were significantly less protective than vaccines inducing only immunodominant-specific responses. These results have important implications for T. cruzi vaccine development. Of broader significance, we demonstrate that increasing breadth of T cell epitope responses induced by vaccination is not always advantageous for host immunity.

Novel Identified HLA-A*0201-Restricted Hantaan Virus Glycoprotein Cytotoxic T-Cell Epitopes Could Effectively Induce Protective Responses in HLA-A2.1/Kb Transgenic Mice May Associate with the Severity of Hemorrhagic Fever with Renal Syndrome

“…Emerging results have revealed that vaccines that strictly elicit immunodominant epitope-specific CTL responses could be more effective against viruses. Vaccines that induce both immunodominant and subdominant epitope responses were significantly less protective than vaccines that only elicited immunodominant epitope-specific responses, suggesting that the increased breadth of T-cell epitope recognition may prevent the induction of optimal protective CTL immunity and reduce the efficiency of host immunity against pathogens ( 43 , 44 ). The secondary CTL expansion in vaccinated mice competes for antigen accessibility on antigen-presenting cells, suppressing the priming of other protective pathogen-specific CTLs ( 45 ) and potentially explaining how subdominant epitope vaccination could reduce immunodominant epitope-induced CTL responses.…”

Trans-sialidase-based vaccine candidate protects against Trypanosoma cruzi infection, not only inducing an effector immune response but also affecting cells with regulatory/suppressor phenotype

“…The amplified sequence was cloned into the pGEM ® -T easy vector (Promega, USA) using a T4 DNA Ligase enzyme (Promega, USA) at 4°C overnight. Then, the plasmids were transformed in E. coli DH5α competent cells as previously described [ 49 ] and mini preparations of pGEM°-T easy vector were obtained using Miniprep isolation columns (QIAGEN, Valencia, CA), following the manufacturer's instructions. After sequencing the plasmids, the identity of the PCR products was verified by alignment with all the TS genes indexed in the GenBank and the particular sequence (AJ276679) that was used to design the primers.…”

Understanding CD8+ T Cell Immunity to Trypanosoma cruzi and How to Improve It

“…These authors propose that even though the naturally-triggered immunity to T. cruzi is strong, vaccination could be exploited to induce CD8 + T cells of improved quality and fitness to cope with the infection. Moreover, a combination of genetic and cell-based immunization approaches allowed to obtain important data related to epitope immunodominance [76]. These authors showed that a DNA vaccine encoding an enzymatically active TS and an immunodominant CD8 + T cell epitope is able to enhance subdominant pathogen-specific CD8 + T cell responses as consequence of a co-stimulatory effect mediated by active TS.…”