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CD8 +  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 1  (AT 1 R), a key effector axis of renin-angiotensin system (RAS), have immune regulatory effects on T cells. Previously, we showed that inhibition of AT 1 R signaling protects mice against the lethal disease induced by  Plasmodium berghei  ANKA infection However, most of the Ang II/AT 1 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 1 R in inducing the pathogenic activity of  Plasmodium -specific CD8 +  T cells during blood-stage were not determined. Here, we examined how angiotensin II/AT 1 R axis promotes the harmful response of  Plasmodium -specific CD8 +  T-cell during blood-stage by using genetic and pharmacological approaches. We evaluated the response of wild-type (WT) and AT 1 R −/−   Plasmodium -specific CD8 +  T cells in mice infected with a transgenic PbA lineage expressing ovalbumin; and in parallel infected mice receiving WT  Plasmodium -specific CD8 +  T cells were treated with losartan (AT 1 R antagonist) or captopril (ACE inhibitor). Both, AT 1 R −/−  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 1 R −/−  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 1 R −/−  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 1 R-induced harmful phenotype of  Plasmodium -specific CD8 +  T cells during blood-stage malaria.

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