AUTHOR=Silva-Filho João L. , Caruso-Neves Celso , Pinheiro Ana A. S. 

TITLE=Targeting Angiotensin II Type-1 Receptor (AT1R) Inhibits the Harmful Phenotype of Plasmodium-Specific CD8+ T Cells during Blood-Stage Malaria

JOURNAL=Frontiers in Cellular and Infection Microbiology

VOLUME=7

YEAR=2017

URL=https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2017.00042

DOI=10.3389/fcimb.2017.00042

ISSN=2235-2988

ABSTRACT=<p>CD8<sup>+</sup> T-cell response is critical in the pathogenesis of cerebral malaria during blood-stage. Our group and other have been shown that angiotensin II (Ang II) and its receptor AT<sub>1</sub> (AT<sub>1</sub>R), a key effector axis of renin-angiotensin system (RAS), have immune regulatory effects on T cells. Previously, we showed that inhibition of AT<sub>1</sub>R signaling protects mice against the lethal disease induced by <italic>Plasmodium berghei</italic> ANKA infection However, most of the Ang II/AT<sub>1</sub>R actions were characterized by using only pharmacological approaches, the effects of which may not always be due to a specific receptor blockade. In addition, the mechanisms of action of the AT<sub>1</sub>R in inducing the pathogenic activity of <italic>Plasmodium</italic>-specific CD8<sup>+</sup> T cells during blood-stage were not determined. Here, we examined how angiotensin II/AT<sub>1</sub>R axis promotes the harmful response of <italic>Plasmodium</italic>-specific CD8<sup>+</sup> T-cell during blood-stage by using genetic and pharmacological approaches. We evaluated the response of wild-type (WT) and AT<sub>1</sub>R<sup>−/−</sup><italic>Plasmodium</italic>-specific CD8<sup>+</sup> T cells in mice infected with a transgenic PbA lineage expressing ovalbumin; and in parallel infected mice receiving WT <italic>Plasmodium</italic>-specific CD8<sup>+</sup> T cells were treated with losartan (AT<sub>1</sub>R antagonist) or captopril (ACE inhibitor). Both, AT<sub>1</sub>R<sup>−/−</sup> OT-I cells and WT OT-I cells from losartan- or captopril-treated mice showed lower expansion, reduced IL-2 production and IL-2Rα expression, lower activation (lower expression of CD69, CD44 and CD160) and lower exhaustion profiles. AT<sub>1</sub>R<sup>−/−</sup> OT-I cells also exhibit lower expression of the integrin LFA-1 and the chemokine receptors CCR5 and CXCR3, known to play a key role in the development of cerebral malaria. Moreover, AT<sub>1</sub>R<sup>−/−</sup> OT-I cells produce lower amounts of IFN-γ and TNF-α and show lower degranulation upon restimulation. In conclusion, our results show the pivotal mechanisms of AT<sub>1</sub>R-induced harmful phenotype of <italic>Plasmodium</italic>-specific CD8<sup>+</sup> T cells during blood-stage malaria.</p>