RESUMO
Introduction: This study provides evidence of how Th1 cell metabolism is modulated by the purinergic receptor P2X7 (P2RX7), a cation cannel activated by high extracellular concentrations of adenosine triphosphate (ATP). Methods: In vivo analysis was performed in the Plasmodium chabaudi model of malaria in view of the great relevance of this infectious disease for human health, as well as the availability of data concerning Th1/Tfh differentiation. Results: We show that P2RX7 induces T-bet expression and aerobic glycolysis in splenic CD4+ T cells that respond to malaria, at a time prior to Th1/Tfh polarization. Cell-intrinsic P2RX7 signaling sustains the glycolytic pathway and causes bioenergetic mitochondrial stress in activated CD4+ T cells. We also show in vitro the phenotypic similarities of Th1-conditioned CD4+ T cells that do not express P2RX7 and those in which the glycolytic pathway is pharmacologically inhibited. In addition, in vitro ATP synthase blockade and the consequent inhibition of oxidative phosphorylation, which drives cellular metabolism for aerobic glycolysis, is sufficient to promote rapid CD4+ T cell proliferation and polarization to the Th1 profile in the absence of P2RX7. Conclusion: These data demonstrate that P2RX7-mediated metabolic reprograming for aerobic glycolysis is a key event for Th1 differentiation and suggest that ATP synthase inhibition is a downstream effect of P2RX7 signaling that potentiates the Th1 response.
Assuntos
Glicólise , Malária , Receptores Purinérgicos P2X7 , Células Th1 , Animais , Camundongos , Camundongos Endogâmicos C57BL , Receptores Purinérgicos P2X7/metabolismo , Células Th1/citologia , Células Th1/metabolismo , Diferenciação Celular , Plasmodium chabaudi , Malária/imunologia , Trifosfato de Adenosina , Adenosina Trifosfatases , Mitocôndrias/metabolismo , Proteínas com Domínio T/metabolismo , Fosforilação Oxidativa , Transdução de Sinais , Células CultivadasRESUMO
During oral infection, mucosal immunity assumes a predominant role. Here, we addressed the role of mast cells (MCs), which are mainly located in mucosa during oral infection with Toxoplasma gondii, using MC-deficient (W/W(v) ) mice. We show that in the absence of MCs the resistance of W/W(v) mice to oral infection was considerably reduced. W/W(v) mice uniformly succumbed within 15 days of infection after administration of cysts of the ME49 strain of T. gondii. The rapid lethality of T. gondii in W/W(v) mice correlated with a delayed Th1-cell response, since IFN-γ and IL-12 levels peaked in the later phase of the infection. In vitro, BM-derived MCs were able to recognize parasite lysate in a MyD88-dependent way, reaffirming the role of this TLR adapter in immune responses to T. gondii. The importance of MCs in vivo was confirmed when W/W(v) mice reconstituted with BM-derived MCs from control mice retrieved an early strong Th1-cell response and specially a significant IL-12 production. In conclusion, MCs play an important role for the development of a protective immune response during oral infection with T. gondii.
Assuntos
Imunidade nas Mucosas/imunologia , Mastócitos/imunologia , Toxoplasmose Animal/imunologia , Animais , Imunofluorescência , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Th1/imunologia , Toxoplasma/imunologiaRESUMO
Any therapeutic vaccination approach against HIV-1 must induce CTL and Th1 cells. But, therapeutic vaccination is more than that. For extensive application of a therapeutic vaccine several questions need to be solved in advance to achieve a global impact. In this commentary some of them are addressed. We analyze the epidemiology, sociology, economy and immunopathology related to the HIV/AIDS disease. Also, important technical issues and real possibilities to overcome at least some of the major limitation of the antiretroviral treatments in the pursuit of an effective vaccine are considered. From the integration of previous analyses some conclusions are drawn. Because it is just a commentary some arguments are not unveiled into their full extension. At the end, we discuss some issues in relation to the development of the vaccine candidate TERAVAC-HIV-1 as a case study.