Purinergic P2X7R expressed on regulatory T cells potentially links molecular mimicry to autoimmune responses

Abstract

<abstract> <p>The immune system is meant to protect against invading microbes. Although this system is effective against many microbes, some can use molecular mimicry to turn the immune system against the host and activate autoimmune responses. The resulting autoimmunity has significant implications for public health and healthcare costs. It is well known that regulatory T cells (Tregs) are crucial for self-tolerance and that their function is impaired after exposure to self-antigens or antigens with molecular mimicry, leading to the activation of autoimmune responses. How molecular mimicry disrupts Tregs in this manner remains under debate. This review contributes to the field of the pathogenesis of autoimmunity by proposing that purinergic signaling in the lymph nodes, with extracellular ATP, ADP, and adenosine as ligands, plays a pivotal role in this process. Repeated or high-dose microbial infection causes the release of large amounts of extracellular ATP sufficient to reach the threshold of extracellular ATP levels for activating P2X7 purinergic receptors (P2X7Rs) on dendritic cells and Tregs. This hampers the ability of Tregs to suppress autoimmune responses. Crucially, P2X7Rs are activated at very high extracellular ATP levels, thus only after repeated or high-dose infection with microbes. Arguably, in contrast to the rapid elimination of microbes with foreign antigens, the clearance of invading microbes that employ molecular mimicry requires the activation of P2X7Rs at the expense of self-tolerance. Because all processes required to activate autoimmune responses occur in secondary lymphoid organs, this article hypothesizes that, contrary to current convention, microbes do not need to enter organs to initiate autoimmunity. However, some types of microbes can prevent P2X7R-induced Treg disruption by converting extracellular ATP to adenosine, mitigating autoimmune responses resulting in chronic diseases with less severe inflammation. The proposed hypothesized mechanism has potential implications for the understanding and treatment of autoimmune disorders.</p> </abstract>