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Immunol."],"abstract":"<jats:p>Cytokines that signal through the JAK-STAT pathway, such as interferon-\u03b3 (IFN-\u03b3) and common \u03b3 chain cytokines, contribute to the destruction of insulin-secreting \u03b2 cells by CD8<jats:sup>+<\/jats:sup>T cells in type 1 diabetes (T1D). We previously showed that JAK1\/JAK2 inhibitors reversed autoimmune insulitis in non-obese diabetic (NOD) mice and also blocked IFN-\u03b3 mediated MHC class I upregulation on \u03b2 cells. Blocking interferons on their own does not prevent diabetes in knockout NOD mice, so we tested whether JAK inhibitor action on signaling downstream of common \u03b3 chain cytokines, including IL-2, IL-7 IL-15, and IL-21, may also affect the progression of diabetes in NOD mice. Common \u03b3 chain cytokines activate JAK1 and JAK3 to regulate T cell proliferation. We used a JAK1-selective inhibitor, ABT 317, to better understand the specific role of JAK1 signaling in autoimmune diabetes. ABT 317 reduced IL-21, IL-2, IL-15 and IL-7 signaling in T cells and IFN-\u03b3 signaling in \u03b2 cells, but ABT 317 did not affect GM-CSF signaling in granulocytes. When given<jats:italic>in vivo<\/jats:italic>to NOD mice, ABT 317 reduced CD8<jats:sup>+<\/jats:sup>T cell proliferation as well as the number of KLRG<jats:sup>+<\/jats:sup>effector and CD44<jats:sup>hi<\/jats:sup>CD62L<jats:sup>lo<\/jats:sup>effector memory CD8<jats:sup>+<\/jats:sup>T cells in spleen. ABT 317 also prevented MHC class I upregulation on \u03b2 cells. Newly diagnosed diabetes was reversed in 94% NOD mice treated twice daily with ABT 317 while still on treatment at 40 days and 44% remained normoglycemic after a further 60 days from discontinuing the drug. Our results indicate that ABT 317 blocks common \u03b3 chain cytokines in lymphocytes and interferons in lymphocytes and \u03b2 cells and are thus more effective against diabetes pathogenesis than IFN-\u03b3 receptor deficiency alone. Our studies suggest use of this class of drug for the treatment of type 1 diabetes.<\/jats:p>","DOI":"10.3389\/fimmu.2020.588543","type":"journal-article","created":{"date-parts":[[2020,12,4]],"date-time":"2020-12-04T04:28:55Z","timestamp":1607056135000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":47,"title":["The JAK1 Selective Inhibitor ABT 317 Blocks Signaling Through Interferon-\u03b3 and Common \u03b3 Chain Cytokine Receptors to Reverse Autoimmune Diabetes in NOD 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