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.

Highlights

  • 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

  • To determine the importance of AT1R in regulating the antigen-specific CD8+ T-cell response, we first evaluated the role of AT1R in the primary clonal expansion and homeostatic contraction of antigen-specific CD8+ T cells induced by immunization with P. berghei CS5M γ-spz

  • Ang II binds 2 different receptors, AT1R and AT2R, previous studies have shown that AT1R expression is upregulated in T cells in vitro and during Plasmodium berghei ANKA (PbA) infection and mediates most of the effects of Ang II in T cells[5,6,7,8,9,10,11,12,13,14,15,18,20,21]

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Summary

Introduction

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. Priming events after immunization were not affected but the expansion and contraction of AT1R-deficient (AT1R−/−) OT-I cells was decreased They seemed more activated, express higher levels of CTLA-4, PD-1, LAG-3, and have decreased functional capacity during the effector phase. AT1R expression is upregulated in T cells during activation in vitro and in vivo, for instance during the blood stage of Plasmodium berghei ANKA (PbA) infection, strengthening the importance of this receptor for T-cell response[11,12,13,15] In this regard, AT1R is involved in the higher production of pro-inflammatory cytokines by CD4+ T cells and perforin by CD8+ T cells, and increased capacity to adhere and migrate through upregulation of adhesion molecules and chemokine receptors[12,13]. There is no clear evidence regarding the role of AT1R expressed by antigen-specific CD8+ T cells regulating their response against pathogens during effector or even memory phases, which requires further exploration

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