P2X7 receptor drives Th1 cell differentiation and controls the follicular helper T cell population to protect against Plasmodium chabaudi malaria

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de Salles, Erika Machado ; de Menezes, Maria Nogueira ; Siqueira, Renan ; da Silva, Henrique Borges ; Amaral, Eduardo Pinheiro ; Castillo-Mendez, Sheyla Ines ; Cunha, Isabela ; Cassado, Alexandra dos Anjos ; Vieira, Flavia Sarmento ; Nicholas Olivieri, David ; Tadokoro, Carlos Eduardo ; Alvarez, Jose Maria ; Coutinho-Silva, Robson ; D'Imperio-Lima, Maria Regina

• Tipo de documento: Artigo Científico
• Fonte: PLOS PATHOGENS; v. 13, n. 8 AUG 2017.
• Citações Web of Science: 15

Resumo

A complete understanding of the mechanisms underlying the acquisition of protective immunity is crucial to improve vaccine strategies to eradicate malaria. However, it is still unclear whether recognition of damage signals influences the immune response to Plasmodium infection. Adenosine triphosphate (ATP) accumulates in infected erythrocytes and is released into the extracellular milieu through ion channels in the erythrocyte membrane or upon erythrocyte rupture. The P2X7 receptor senses extracellular ATP and induces CD4 T cell activation and death. Here we show that P2X7 receptor promotes T helper 1 (Th1) cell differentiation to the detriment of follicular T helper (Tfh) cells during blood-stage Plasmodium chabaudi malaria. The P2X7 receptor was activated in CD4 T cells following the rupture of infected erythrocytes and these cells became highly responsive to ATP during acute infection. Moreover, mice lacking the P2X7 receptor had increased susceptibility to infection, which correlated with impaired Th1 cell differentiation. Accordingly, IL-2 and IFN gamma secretion, as well as T-bet expression, critically depended on P2X7 signaling in CD4 T cells. Additionally, P2X7 receptor controlled the splenic Tfh cell population in infected mice by promoting apoptotic-like cell death. Finally, the P2X7 receptor was required to generate a balanced Th1/Tfh cell population with an improved ability to transfer parasite protection to CD4-deficient mice. This study provides a new insight into malaria immunology by showing the importance of P2X7 receptor in controlling the fine-tuning between Th1 and Tfh cell differentiation during P. chabaudi infection and thus in disease outcome. (AU)

• Processo FAPESP: 10/51150-4 - Modelo nimal para análise da patogenicidade de cepas de Mycobacterium bovis e avaliação da resposta imune celular e humoral contra isolados patogênicos
• Beneficiário: Maria Regina D'Império Lima
• Linha de fomento: Auxílio à Pesquisa - Regular
• Processo FAPESP: 15/20432-8 - Intervenção em vias de sinalização associadas ao reconhecimento de dano celular visando reduzir a patologia das formas graves de malária e tuberculose
• Beneficiário: Maria Regina D'Império Lima
• Linha de fomento: Auxílio à Pesquisa - Temático
• Processo FAPESP: 13/07140-2 - Papel dos inflamassomas na patogenia da tuberculose causada por isolados clínicos hipervirulentos de micobactérias
• Beneficiário: Maria Regina D'Império Lima
• Linha de fomento: Auxílio à Pesquisa - Regular
• Processo FAPESP: 11/11053-2 - Efeitos da sinalização purinérgica durante a infecção aguda e crônica pelo Plasmodium chabaudi AS
• Beneficiário: Érika Machado de Salles
• Linha de fomento: Bolsas no Brasil - Doutorado