Rapamycin Improves the Response of Effector and Memory CD8+ T Cells Induced by Immunization With ASP2 of Trypanosoma cruzi
| Autor: | Barbara Ferri Moraschi, Isaú Henrique Noronha, Camila Pontes Ferreira, Leonardo M. Cariste, Caroline B. Monteiro, Priscila Denapoli, Talita Vrechi, Gustavo J. S. Pereira, Ricardo T. Gazzinelli, Joseli Lannes-Vieira, Maurício M. Rodrigues, Karina R. Bortoluci, José Ronnie C. Vasconcelos |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Microbiology (medical) effector CD8+ T cells Trypanosoma cruzi medicine.medical_treatment Immunology Population Biology Microbiology 03 medical and health sciences 0302 clinical medicine In vivo vaccine medicine Cytotoxic T cell Interferon gamma VACINAÇÃO education PI3K/AKT/mTOR pathway education.field_of_study rapamycin CD8+ T-cells biology.organism_classification QR1-502 030104 developmental biology Infectious Diseases mTOR Adjuvant CD8 030215 immunology medicine.drug |
| Zdroj: | Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP Frontiers in Cellular and Infection Microbiology, Vol 11 (2021) |
| ISSN: | 2235-2988 |
| DOI: | 10.3389/fcimb.2021.676183 |
| Popis: | Deficiency in memory formation and increased immunosenescence are pivotal features of Trypanosoma cruzi infection proposed to play a role in parasite persistence and disease development. The vaccination protocol that consists in a prime with plasmid DNA followed by the boost with a deficient recombinant human adenovirus type 5, both carrying the ASP2 gene of T. cruzi, is a powerful strategy to elicit effector memory CD8+ T-cells against this parasite. In virus infections, the inhibition of mTOR, a kinase involved in several biological processes, improves the response of memory CD8+ T-cells. Therefore, our aim was to assess the role of rapamycin, the pharmacological inhibitor of mTOR, in CD8+ T response against T. cruzi induced by heterologous prime-boost vaccine. For this purpose, C57BL/6 or A/Sn mice were immunized and daily treated with rapamycin for 34 days. CD8+ T-cells response was evaluated by immunophenotyping, intracellular staining, ELISpot assay and in vivo cytotoxicity. In comparison with vehicle-injection, rapamycin administration during immunization enhanced the frequency of ASP2-specific CD8+ T-cells and the percentage of the polyfunctional population, which degranulated (CD107a+) and secreted both interferon gamma (IFNγ) and tumor necrosis factor (TNF). The beneficial effects were long-lasting and could be detected 95 days after priming. Moreover, the effects were detected in mice immunized with ten-fold lower doses of plasmid/adenovirus. Additionally, the highly susceptible to T. cruzi infection A/Sn mice, when immunized with low vaccine doses, treated with rapamycin, and challenged with trypomastigote forms of the Y strain showed a survival rate of 100%, compared with 42% in vehicle-injected group. Trying to shed light on the biological mechanisms involved in these beneficial effects on CD8+ T-cells by mTOR inhibition after immunization, we showed that in vivo proliferation was higher after rapamycin treatment compared with vehicle-injected group. Taken together, our data provide a new approach to vaccine development against intracellular parasites, placing the mTOR inhibitor rapamycin as an adjuvant to improve effective CD8+ T-cell response. |
| Databáze: | OpenAIRE |
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