One of the best defined ?danger? signals, that alerts the innate immune system to cellular damage, is extracellular ATP, triggering ion flux through the purinergic receptor P2RX7. The roles of P2RX7 in the adaptive immune system, by contrast, are less clear. We recently showed that P2RX7 was essential for production and maintenance of long-lived CD8+ T cell memory. This involved P2RX7 signals promoting the establishment of mitochondrial maintenance and metabolic ?fitness? in differentiating memory CD8+ T cells, but we also found evidence that sustained P2RX7 signals are needed to sustain pre-existing memory CD8+ T cells, suggesting this ?danger? signal is repurposed to provide a homeostatic survival signal for CD8+ T cells. Much remains to be understood about how P2RX7 signaling influences T cell memory, however.
In Aim 1, we turn our attention to CD4+ T cells: while P2RX7 is critical for generation of memory CD8+ T cells, certain subsets of memory CD4+ T cells (including follicular helper-like central memory cells), show increased survival when P2rx7 is ablated ? we explore the basis for these differential effects of P2RX7 stimulation on CD4+ and CD8+ memory T cell subsets.
In Aim 2, we explore how memory CD8+ T cells may be able to provide autocrine stimulation of P2RX7 through export of their ?own? ATP, through the Pannexin 1 channel. Finally, P2RX7 has been shown to play an important role in another area of biology ? in chronic pain. Sustained stimulation of P2RX7 on innate immune cells is thought to be responsible for various forms of neuropathic and inflammatory pain (associated with nerve damage, autoimmune diseases, cancer, etc.) and pharmacological blockade of P2RX7 has been shown in animal models to alleviate such chronic pain. This raises the key question of whether use of such therapeutic blockade leads to degradation of pre-existing T cell memory - in particular, whether such treatment would impair CD8+ T cell mediated control of persistent viral infections. We address this in Aim 3, also investigating whether directed stimulation (rather than blockade) of P2RX7 can be used as a viable way to improve the generation of long-lived CD8+ T cell memory and potentially to enhance control of chronic viral infections but may also dysregulate the CD4+ T cell memory compartment. Together, these studies represent a novel and highly significant investigation into how an innate immune trigger is co-opted into regulating adaptive immune memory, and how this pathway can be harnessed for therapeutic goals with possible application to the clinic.
The immune system is divided into two main groups ? innate immune cells which recognize infections or cellular damage (?danger? signals) and conduct initial responses, and adaptive immune cells, which take more time to respond but which produce potent and specific responses to control pathogens and provide life-long immunity or ?memory? against reinfection. A well-studied innate immune ?danger? signal is ATP ? which is crucial for cellular metabolism but when it is exposed to the outer surface of cells can induce innate immune activation. We recently found that P2RX7, a key receptor for extracellular ATP (eATP), appears to play a critical role in supporting long lived T lymphocyte memory. This sharing of receptors between innate and adaptive immune cells was unexpected and leads to critical questions about how P2RX7 functions in the context of preserving memory T cells. In addition, P2RX7 is involved in chronic pain, as shown by promising results in animal models in which pharmacological blockade of P2RX7 leads to relief from neuropathic or inflammatory pain. This raises the important question of whether pharmacological treatments designed to control neuropathic pain may, inadvertently, cause degradation of protective immunity. These questions will be addressed in the proposal.
