Self-Regulation of Memory CD8 T Cell Metabolism through Extracellular ATP Signaling.

Following activation, CD8 T cells transition from reliance on mitochondrial respiration to increasing utilization of aerobic glycolysis. After the effector phase, however, reversion to mitochondrial metabolism is pivotal generating memory CD8 T cells. We recently showed that sensing of extracellular ATP (eATP) through the receptor P2RX7 is crucial for both production and the long-term survival of memory CD8 T cells, evidently through promoting mitochondrial maintenance. Unexpectedly, these results indicated that sustained P2RX7 activation is required for memory CD8 T cell homeostasis, suggesting constant exposure to eATP, in contrast with the proposed role of eATP as an acute "danger" signal released by dying cells. Active release through transmembrane channels is another path for eATP export. Indeed, CD8 T cells express Pannexin 1 (Panx1) which has a reported eATP release function in vitro and is itself induced by P2RX7 and/or TCR engagement. Such a role for Panx1 could potentially provide a feed-forward mechanism for cell-autonomous P2RX7 signaling. This model envisages that memory CD8 T cells maintain themselves at the cost of reduced intracellular ATP levels, which at first glance would seem to be detrimental for sustained T cell maintenance. On the other hand, the need to tightly regulate levels of intracellular ATP may be critical for the durability and adaptability of memory CD8 T cells, hence engagement of the P2RX7/Panx1 axis may allow these cells to fine tune their metabolic status to meet changing demands. In this Perspective, we discuss how this pathway may influence memory T cell maintenance.

IFN-γ-induced priming maintains long-term strain-transcending immunity against blood-stage Plasmodium chabaudi malaria.

The mechanism by which protective immunity to Plasmodium is lost in the absence of continued exposure to this parasite has yet to be fully elucidated. It has been recently shown that IFN-γ produced during human and murine acute malaria primes the immune response to TLR agonists. In this study, we investigated whether IFN-γ-induced priming is important to maintain long-term protective immunity against Plasmodium chabaudi AS malaria. On day 60 postinfection, C57BL/6 mice still had chronic parasitemia and efficiently controlled homologous and heterologous (AJ strain) challenge. The spleens of chronic mice showed augmented numbers of effector/effector memory (TEM) CD4(+) cells, which is associated with increased levels of IFN-γ-induced priming (i.e., high expression of IFN-inducible genes and TLR hyperresponsiveness). After parasite elimination, IFN-γ-induced priming was no longer detected and protective immunity to heterologous challenge was mostly lost with >70% mortality. Spontaneously cured mice had high serum levels of parasite-specific IgG, but effector T/TEM cell numbers, parasite-driven CD4(+) T cell proliferation, and IFN-γ production were similar to noninfected controls. Remarkably, the priming of cured mice with low doses of IFN-γ rescued TLR hyperresponsiveness and the capacity to control heterologous challenge, increasing the TEM cell population and restoring the CD4(+) T cell responses to parasites. Contribution of TLR signaling to the CD4(+) T cell responses in chronic mice was supported by data obtained in mice lacking the MyD88 adaptor. These results indicate that IFN-γ-induced priming is required to maintain protective immunity against P. chabaudi and aid in establishing the molecular basis of strain-transcending immunity in human malaria.

Early skin immunological disturbance after Plasmodium-infected mosquito bites.

Although the role of regulatory T cells (Tregs) during malaria infection has been studied extensively, such studies have focused exclusively on the role of Treg during the blood stage of infection; little is known about the detailed mechanisms of Tregs and sporozoite deposition in the dermis by mosquito bites. In this paper we show that sporozoites introduced into the skin by mosquito bites increase the mobility of skin Tregs and dendritic cells (DCs). We also show differences in MHC class II and/or CD86 expression on skin-resident dendritic cell subtypes and macrophages. From the observed decrease of the number of APCs into draining lymph nodes, suppression of CD28 expression in conventional CD4 T cells, and a low homeostatic proliferation of skin-migrated CD4 T found in nude mice indicate that Tregs may play a fundamental role during the initial phase of malaria parasite inoculation into the mammalian host.