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

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

Author Eickhoff, Christopher S. Google Scholar
Zhang, Xiuli Google Scholar
Vasconcelos, Jose R. Autor UNIFESP Google Scholar
Motz, R. Geoffrey Google Scholar
Sullivan, Nicole L. Google Scholar
O'Shea, Kelly Google Scholar
Pozzi, Nicola Google Scholar
Gohara, David W. Google Scholar
Blase, Jennifer R. Google Scholar
Di Cera, Enrico Google Scholar
Hoft, Daniel F. Google Scholar
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.
Language English
Sponsor National Institutes of Health [5R01AI040196, 2R56AI040196, 5R21AI099514]
EDC [HL049413, HL073813, HL112303]
Fundacao de Amparo a Pesquisa do Estado de Sao Paulo [2012/22514-3]
Grant number NIH:5R01AI040196
2R56AI040196
5R21AI099514
EDC:HL049413
HL073813
HL112303
FAPESP:2012/22514-3
Date 2016
Published in Plos Pathogens. San Francisco, v. 12, n. 9, p. -, 2016.
ISSN 1553-7366 (Sherpa/Romeo, impact factor)
Publisher Public Library Science
Extent -
Origin http://dx.doi.org/10.1371/journal.ppat.1005896
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000385621900053
URI http://repositorio.unifesp.br/handle/11600/51069

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