Angiotensin II type-1 receptor (AT1R) regulates expansion, differentiation, and functional capacity of antigen-specific CD8+ T cells

Abstract

Angiotensin II (Ang II) and its receptor AT1 (AT1R), an important effector axis of renin-angiotensin system (RAS), have been demonstrated to regulate T-cell responses. However, these studies characterized Ang II and AT1R effects using pharmacological tools, which do not target only Ang II/AT1R axis. The specific role of AT1R expressed by antigen-specific CD8+ T cells is unknown. Then we immunized transgenic mice expressing a T-cell receptor specific for SIINFEKL epitope (OT-I mice) with sporozoites of the rodent malaria parasite Plasmodium berghei expressing the cytotoxic epitope SIINFEKL. Early priming events after immunization were not affected but the expansion and contraction of AT1R-deficient (AT1R−/−) OT-I cells was decreased. Moreover, they seemed more activated, express higher levels of CTLA-4, PD-1, LAG-3, and have decreased functional capacity during the effector phase. Memory AT1R−/− OT-I cells exhibited higher IL-7Rα expression, activation, and exhaustion phenotypes but less cytotoxic capacity. Importantly, AT1R−/− OT-I cells show better control of blood parasitemia burden and ameliorate mice survival during lethal disease induced by blood-stage malaria. Our study reveals that AT1R in antigen-specific CD8+ T cells regulates expansion, differentiation, and function during effector and memory phases of the response against Plasmodium, which could apply to different infectious agents.

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

“…In turn, CD8 + T cells promote cerebral edema, cognitive impairment, and lethal disease (Silva-Filho et al, 2011 , 2013 ). In contrast, more recently, we showed that AT 1 R signaling induces expansion but dampens the activation and exhaustion of antigen-specific CD8 + T cells during the effector response to whole-parasite immunization (Silva-Filho et al, 2016 ). Also, effector cells lacking AT 1 R generate a higher number of memory cells, which is an important factor to limit parasite development in the liver (Silva-Filho et al, 2016 ).…”

“…In contrast, more recently, we showed that AT 1 R signaling induces expansion but dampens the activation and exhaustion of antigen-specific CD8 + T cells during the effector response to whole-parasite immunization (Silva-Filho et al, 2016 ). Also, effector cells lacking AT 1 R generate a higher number of memory cells, which is an important factor to limit parasite development in the liver (Silva-Filho et al, 2016 ). So, it seems that the intrinsic role and function of AT 1 R in CD8 + T cells could be stage dependent, decreasing the protective response during immunization with liver-stage parasites but stimulating the harmful response during infection with blood-stage parasites.…”

“…However, studies have shifted the attention toward its nonclassic effects, and Ang II has been proposed to be central in the inflammatory aspects of different diseases (Bush et al, 2000 ; Donadelli et al, 2000 ). Previously, our group and others have demonstrated that T cells express a functional RAS that produces and responds to Ang II mainly via AT 1 R (Kunertradek et al, 1994 ; Nataraj et al, 1999 ; Inoue et al, 2006 ; Guzik et al, 2007 ; Jurewicz et al, 2007 ; Hoch et al, 2008 ; Platten et al, 2009 ; Silva-Filho et al, 2011 , 2013 , 2015 , 2016 ; Zhang et al, 2012 ). AT 1 R expression is upregulated in polyclonal T cells during the blood-stage of PbA infection, and it stimulates the production of perforin and migration/sequestration of polyclonal CD8 + T cells in the brain.…”

“…So, it seems that the intrinsic role and function of AT 1 R in CD8 + T cells could be stage dependent, decreasing the protective response during immunization with liver-stage parasites but stimulating the harmful response during infection with blood-stage parasites. Indeed, inhibition of AT 1 R only in Plasmodium -specific CD8 + T cells promoted better control of blood parasitemia and improved survival of mice against the lethal disease induced by blood-stage malaria (Silva-Filho et al, 2016 ). In agreement, pharmacological blockade of AT 1 R protected mice against ECM and increased survival (Silva-Filho et al, 2013 ; Gallego-Delgado et al, 2016 ).…”

“…Here, we examined the mechanisms of action of AT 1 R specifically in the Plasmodium -specific CD8 + T-cell response during blood-stage malaria, by using wild-type (WT; AT 1 R +/+ ) or AT 1 R −/− CD8 + T cells from ovalbumin (OVA)-specific TCR transgenic mice (OT-I), which allow the tracking of the antigen-specific CD8 + T cell response (Lundie et al, 2008 ; Miyakoda et al, 2008 ; Cockburn et al, 2010 ; Chen and Zavala, 2013 ; Silva-Filho et al, 2016 ). In parallel, to complement the genetic approach, we also tested the effects of two drugs that block the AT 1 R response, losartan (AT 1 R antagonist) or captopril (inhibitor of Ang II production), in mice that received WT OT-I cells.…”