title: Targeting Angiotensin II Type-1 Receptor (AT1R) Inhibits the Harmful Phenotype ofPlasmodium-Specific CD8+T Cells during Blood-Stage Malaria.
abstract: 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 AT1(AT1R), a key effector axis of renin-angiotensin system (RAS), have immune regulatory effects on T cells. Previously, we showed that inhibition of AT1R signaling protects mice against the lethal disease induced byPlasmodium bergheiANKA infection However, most of the Ang II/AT1R 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 AT1R in inducing the pathogenic activity ofPlasmodium-specific CD8+T cells during blood-stage were not determined. Here, we examined how angiotensin II/AT1R axis promotes the harmful response ofPlasmodium-specific CD8+T-cell during blood-stage by using genetic and pharmacological approaches. We evaluated the response of wild-type (WT) and AT1R-/-Plasmodium-specific CD8+T cells in mice infected with a transgenic PbA lineage expressing ovalbumin; and in parallel infected mice receiving WTPlasmodium-specific CD8+T cells were treated with losartan (AT1R antagonist) or captopril (ACE inhibitor). Both, AT1R-/-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. AT1R-/-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, AT1R-/-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 AT1R-induced harmful phenotype ofPlasmodium-specific CD8+T cells during blood-stage malaria.
authors.affiliation: Laboratório de Bioquímica e Sinalização Celular, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro Rio de Janeiro, Brazil.
authors.forename: João L
authors.initials: JL
authors.lastname: Silva-Filho
authors.affiliation: Laboratório de Bioquímica e Sinalização Celular, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de JaneiroRio de Janeiro, Brazil; Instituto Nacional de Ciência e Tecnologia em Biologia e Bioimagem, Conselho Nacional de Desenvolvimento Científico e Tecnológico/MCTRio de Janeiro, Brazil.
authors.forename: Celso
authors.initials: C
authors.lastname: Caruso-Neves
authors.affiliation: Laboratório de Bioquímica e Sinalização Celular, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de JaneiroRio de Janeiro, Brazil; Instituto Nacional para Pesquisa Translacional em Saúde e Ambiente na Região Amazônica, Conselho Nacional de Desenvolvimento Científico e Tecnológico/MCTRio de Janeiro, Brazil.
authors.forename: Ana A S
authors.initials: AA
authors.lastname: Pinheiro
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D015550:Cell Degranulation / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D007376:Interleukin-2 / Q000096:biosynthesis; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008018:Life Cycle Stages; D008213:Lymphocyte Activation / Q000276:immunology; D008288:Malaria / Q000276:immunology* / Q000378:metabolism* / Q000469:parasitology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D010961:Plasmodium / Q000502:physiology*; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism*; D019707:Receptors, Chemokine / Q000378:metabolism
chemical_list: D016207:Cytokines; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D044140:Receptor, Angiotensin, Type 1; D019707:Receptors, Chemokine
keywords: AT1 receptor; CD8+ T cells; angiotensin; blood-stage; malaria