Rapamycin Improves the Response of Effector and Memory CD8+ T Cells Induced by Immunization With ASP2 of Trypanosoma cruzi

Abstract

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.

Expression of γ-globin genes in β-thalassemia patients treated with sirolimus: results from a pilot clinical trial (Sirthalaclin)

“…In addition, we were able to study the effects of sirolimus on the biological activity of memory T cells (Figure 9) when stimulated by CEF peptides (mimicking sequences of the proteins of cytomegalovirus, Epstein-Barr virus, and Influenza A virus). This study might help to understand whether sirolimus could be effective in sustaining the long-term effects of vaccination, as recently reported 97,98 (unpublished data from Matteo Zurlo). Finally, when the results of the THALA-RAP trial (NCT04247750, focusing on β 0 /β 0 and β 0 /β + thalassemia patients) are available, we might relate genotypes with the effects on HbF production and transfusion demand.…”

Pleiotropic effects of antibiotics on T cell metabolism and T cell-mediated immunity

“…Rapamycin was shown to improve the effector and memory CD8 + T cell responses following immunization with the ASP2 protein of Trypanosoma cruzi (Moraschi et al, 2021).…”

“…Similar to CD4 + T cells, rapamycin also modulates CD8 + T cell function. Rapamycin was reported to mediate the formation of memory CD8 + T cells in vitro ( Araki et al, 2009 ; Pedicord et al, 2015 ; Moraschi et al, 2021 ). Furthermore, during vaccination of non-human primates, rapamycin enhanced CD8 + memory T cell responses in the expansion and contraction phase ( Araki et al, 2009 ), which was associated with a loss of T-bet but a compensatory upregulation of the transcription factor Eomes, which regulates T-cell homeostasis and function ( Rao et al, 2010 ; Figure 3 ).…”

“…Rapamycin was shown to improve the effector and memory CD8 + T cell responses following immunization with the ASP2 protein of Trypanosoma cruzi ( Moraschi et al, 2021 ). Here, rapamycin increased proliferation and cytotoxicity and stabilized effector, central memory, and effector memory CD8 + T cells.…”

“…Here, rapamycin increased proliferation and cytotoxicity and stabilized effector, central memory, and effector memory CD8 + T cells. In addition, IFN-γ, TNF-α, and CD107a expression in CD8 + T cells appeared higher in the presence of rapamycin ( Moraschi et al, 2021 ). Furthermore, rapamycin also increased the number of CD8 + virus-specific T cells after acute lymphocytic choriomeningitis ( Araki et al, 2009 ).…”