Editorial: Extracellular Nucleotides in Lymphocyte Function

The optimal function of lymphocytes (e.g., T and B cells) requires the sensing of a plethora of signals, many of them coming from the extracellular environment. Many of these signals are actively produced and secreted by immune and non-immune cells, e.g., cytokines (Nolz and Richer, 2020). In addition, the passive release of intracellular metabolites plays an important role in regulating lymphocyte function and homeostasis. A prominent class of these metabolites comprises extracellular nucleotides, such as ATP. Release of extracellular ATP (eATP) is often understood as a “danger signal,” i.e., a factor that typifies a situation of threat to the host in face of a disturbance: infections, cancer, or autoimmunity (Di Virgilio et al., 2017). The signaling role of eATP is welldefined for innate immune cells as a crucial activator of the NLRP3 inflammasome (Mariathasan et al., 2006). In the last couple of decades, however, a growing body of work has highlighted the importance of signaling through eATP (and other extracellular nucleotides) for lymphocyte function. In this Special Issue, we present a mix of literature reviews and primary research shedding light on the latest advances in our understanding of this important subject. Release of eATP occurs at particularly high levels inside solid tumors, constituting a fundamental part of the tumor microenvironment (TME). Despite this prevalence, only recently the role of eATP signaling in regulating antitumor lymphocyte function has been done, especially focusing on T cells. The eATP receptor with the most well-defined immune function is the low-affinity P2RX7 ion channel (Di Virgilio et al., 2017). P2RX7 is expressed in antigen-experienced T cells, including those infiltrating solid tumors (Di Virgilio et al., 2017). Curiously, both the wild-type and mutant forms of P2RX7 are expressed at high levels by tumor cells themselves, with a seemingly pro-tumorigenic role. The concomitant expression of this receptor by tumor and T cells in the same TME makes it hard to predict and interpret how manipulation of this signaling pathway would influence the antitumoral T cell responses. The Perspective article by Grassi and Conti provides a comprehensive overview of the recent research and potential future directions on this subject. The association between P2RX7 and cancer is not limited to solid tumors, however. Perhaps linked to its expression in lymphocytes, P2RX7 is found to be expressed in certain hematologic tumor cells, such as leukemic cells. In fact, some of first connections between P2RX7 and oncogenesis were found on lymphocytic leukemia (Wiley and Dubyak, 1989). The Mini Review by De Marchi et al. shows the previous and recent discoveries on this subject and speculates about unanswered questions. P2RX7 is expressed in many distinct lymphocyte subsets, and recent research has unveiled how this receptor regulates these subsets (Di Virgilio et al., 2017). This is especially true for “helper” CD4 T cells: it is now understood that P2RX7 promotes the cell death of regulatory T cells (Treg) and follicular helper T cells (Tfh) (Taylor et al., 2007; Proietti et al., 2014). In contrast, P2RX7 has a Edited and reviewed by: Ana Cuenda, Spanish National Research Council (CSIC), Spain