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Extracellular ATP (eATP) activates T cells by engaging the P2X7R receptor. We identified two loss-of-function P2X7R mutations that are protective against type 1 diabetes (T1D) and thus hypothesized that eATP/P2X7R signaling may represent an early step in T1D onset. Specifically, we observed that in patients with newly diagnosed T1D, P2X7R is upregulated on CD8+ effector T cells in comparison with healthy control subjects. eATP is released at high levels by human/murine islets in vitro in high-glucose/inflammatory conditions, thus upregulating P2X7R on CD8+ T cells in vitro. P2X7R blockade with oxidized ATP reduces the CD8+ T cell-mediated autoimmune response in vitro and delays diabetes onset in NOD mice. Autoreactive CD8+ T-cell activation is highly dependent upon eATP/P2X7R-mediated priming, while a novel sP2X7R recombinant protein abrogates changes in metabolism and the autoimmune response associated with CD8+ T cells. eATP/P2X7R signaling facilitates the onset of autoimmune T1D by fueling autoreactive CD8+ cells and therefore represents a novel targeted therapeutic for the disorder. [ABSTRACT FROM AUTHOR]

OBJECTIVE--The gut environment modulates the pathogenesis of type 1 diabetes (T1D), but how it affects autoimmunity toward pancreatic β-cells, a self-tissue located outside the intestine, is still unclear. In the small intestine, lamina propria dendritic cells (LPDCs) induce peripheral differentiation of FoxP3+ regulatory T (Treg) cells. We tested the hypothesis that the intestinal milieu impinges on human T1D by affecting differentiation of FoxP3+ Treg cells. RESEARCH DESIGN AND METHODS--We collected duodenal biopsies of 10 T1D patients, 16 healthy subjects, and 20 celiac individuals and performed a fluorescent-activated cell sorter analysis to measure percentages of various immune cell subsets, including CD4+ and CD8+ T cells, NK cells, γδ T cells, CD103+CD11c+ LPDCs, and CD4+CD25+FoxP3+CD127- Treg cells. In parallel, we assessed the tolerogenic function (i.e., capacity to induce differentiation of FoxP3+ Treg cells) by LPDCs of T1D patients and control subjects. RESULTS--Our analysis revealed a significant reduction in the percentage of intestinal CD4+CD25+FoxP3+CD127- Treg cells in T1D patients compared with healthy subjects (P = 0.03) and celiac individuals (P = 0.003). In addition, we found that LPDCs from T1D patients completely lacked their tolerogenic function; they were unable to convert CD4+CD25- T cells into CD4+CD25+FoxP3+CD127- Treg cells. CONCLUSIONS--Our data indicate that T1D patients have a reduced number of intestinal FoxP3+ Treg cells as a result of their defective differentiation in the gut. These findings suggest that intestinal immune regulation is not only calibrated to tolerate commensal bacteria and food components but also is instrumental in maintaining immune tolerance toward pancreatic β-cells and preventing T1D. [ABSTRACT FROM AUTHOR]

Extracellular ATP (eATP) activates T cells by engaging the P2X7R receptor. We identified two loss-of-function P2X7R mutations that are protective against type 1 diabetes (T1D) and thus hypothesized that eATP/P2X7R signaling may represent an early step in T1D onset. Specifically, we observed that in patients with newly diagnosed T1D, P2X7R is upregulated on CD8 + effector T cells in comparison with healthy control subjects. eATP is released at high levels by human/murine islets in vitro in high-glucose/inflammatory conditions, thus upregulating P2X7R on CD8 + T cells in vitro. P2X7R blockade with oxidized ATP reduces the CD8 + T cell-mediated autoimmune response in vitro and delays diabetes onset in NOD mice. Autoreactive CD8 + T-cell activation is highly dependent upon eATP/P2X7R-mediated priming, while a novel sP2X7R recombinant protein abrogates changes in metabolism and the autoimmune response associated with CD8 + T cells. eATP/P2X7R signaling facilitates the onset of autoimmune T1D by fueling autoreactive CD8 + cells and therefore represents a novel targeted therapeutic for the disorder., (© 2018 by the American Diabetes Association.)