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

Abstract

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 IFNγ 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.

The yin and yang functions of extracellular ATP and adenosine in tumor immunity

“…eATP released by commensal bacteria was also found to drive the differentiation of intestinal CD4 + T cells to Th17 cells [1]. Another study confirmed that the activation of P2X7R on follicular helper T (Tfh) cells weakened germinal center reactions and immune globulin (Ig) A secretion, and resulted in increased serum IgM [46].…”

“…For T cells, P2X7R is found to distribute uniformly across the cell surface and can be activated by high concentration of eATP, occurring in damaged tissue and under cellular stress. This feature of P2X7R facilitates T cells to distinguish damaged tissues, especially in TME [46]. P2X7R also plays important roles in eATP (100-300 μM) stimulated mitogen-induced CD4 + and CD8 + T cells proliferation.…”

Adaptive Immune Responses Mediated Age-related Plasmodium yoelii 17XL and 17XNL Infections in 4 and 8-week-old BALB/c Mice

“…Further studies are needed to investigate if any shift exists during the early stage of malaria infection. In addition, follicular T helper (Tfh) cells are essential for Plasmodium infection clearance by activating germinal center B cell responses [36,37,38,39]. In this study, the percentage of CD4 + CXCR5 + Tfh cells was also up-regulated in adult mice as compared to the infant group.…”

Recent Insights into CD4+ Th Cell Differentiation in Malaria

“…To our knowledge this has yet to be examined during malaria, although our recent study confirmed that Plasmodium-specific CD4 + T cells dramatically upregulated aerobic glycolysis-related genes as they expand in vivo, and that the emergence of Th1 cells coincides with further acceleration in cell-cycling speed (69). In another study this year, a receptor for extracellular ATP, P2X7, was expressed by CD4 + T cells in mice, and was associated with promoting Th1 differentiation over Tfh development (108). Finally, although chemokine receptors have long been studied on T cells in malaria, their expression on Th cells has tended to be associated with their capacity to migrate to nonlymphoid tissues, such as to the brain, in experimental cerebral malaria (109)(110)(111)(112)(113).…”