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The JAK1 Selective Inhibitor ABT 317 Blocks Signaling Through Interferon-? and Common ? Chain Cytokine Receptors to Reverse Autoimmune Diabetes in NOD Mice.

ABSTRACT: Cytokines that signal through the JAK-STAT pathway, such as interferon-? (IFN-?) and common ? chain cytokines, contribute to the destruction of insulin-secreting ? cells by CD8⁺ 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-? mediated MHC class I upregulation on ? 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 ? chain cytokines, including IL-2, IL-7 IL-15, and IL-21, may also affect the progression of diabetes in NOD mice. Common ? 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-? signaling in ? cells, but ABT 317 did not affect GM-CSF signaling in granulocytes. When given in vivo to NOD mice, ABT 317 reduced CD8⁺ T cell proliferation as well as the number of KLRG⁺ effector and CD44^hiCD62L^lo effector memory CD8⁺ T cells in spleen. ABT 317 also prevented MHC class I upregulation on ? 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 ? chain cytokines in lymphocytes and interferons in lymphocytes and ? cells and are thus more effective against diabetes pathogenesis than IFN-? receptor deficiency alone. Our studies suggest use of this class of drug for the treatment of type 1 diabetes.

SUBMITTER: Ge T

PROVIDER: S-EPMC7746546 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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The JAK1 Selective Inhibitor ABT 317 Blocks Signaling Through Interferon-γ and Common γ Chain Cytokine Receptors to Reverse Autoimmune Diabetes in NOD Mice.

Ge Tingting T Jhala Gaurang G Fynch Stacey S Akazawa Satoru S Litwak Sara S Pappas Evan G EG Catterall Tara T Vakil Ishan I Long Andrew J AJ Olson Lisa M LM Krishnamurthy Balasubramanian B Kay Thomas W TW Thomas Helen E HE

Frontiers in immunology 20201204

Cytokines that signal through the JAK-STAT pathway, such as interferon-γ (IFN-γ) and common γ chain cytokines, contribute to the destruction of insulin-secreting β cells by CD8<sup>+</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-γ mediated MHC class I upregulation on β cells. Blocking interferons on their own does not prevent diabetes in knockout NOD mice, so we tested whe ...[more]

PMID: 33343569

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Project description:The Janus kinase-signal transducer and activator of transcription protein (JAK-STAT) pathway mediates essential biological functions from immune responses to haematopoiesis. Deregulated JAK-STAT signaling causes myeloproliferative neoplasms, leukaemia, and lymphomas, as well as autoimmune diseases. Thereby JAKs have gained significant relevance as therapeutic targets. However, there is still a clinical need for better JAK inhibitors and novel strategies targeting regions outside the conserved kinase domain have gained interest. In-depth knowledge about the molecular details of JAK activation is required. For example, whether the function and regulation between receptors is conserved remains an open question. We used JAK-deficient cell-lines and structure-based mutagenesis to study the function of JAK1 and its pseudokinase domain (JH2) in cytokine signaling pathways that employ JAK1 with different JAK heterodimerization partner. In interleukin-2 (IL-2)-induced STAT5 activation JAK1 was dominant over JAK3 but in interferon-γ (IFNγ) and interferon-α (IFNα) signaling both JAK1 and heteromeric partner JAK2 or TYK2 were both indispensable for STAT1 activation. Moreover, IL-2 signaling was strictly dependent on both JAK1 JH1 and JH2 but in IFNγ signaling JAK1 JH2 rather than kinase activity was required for STAT1 activation. To investigate the regulatory function, we focused on two allosteric regions in JAK1 JH2, the ATP-binding pocket and the αC-helix. Mutating L633 at the αC reduced basal and cytokine induced activation of STAT in both JAK1 wild-type (WT) and constitutively activated mutant backgrounds. Moreover, biochemical characterization and comparison of JH2s let us depict differences in the JH2 ATP-binding and strengthen the hypothesis that de-stabilization of the domain disturbs the regulatory JH1-JH2 interaction. Collectively, our results bring mechanistic understanding about the function of JAK1 in different receptor complexes that likely have relevance for the design of specific JAK modulators.

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Dataset Information

The JAK1 Selective Inhibitor ABT 317 Blocks Signaling Through Interferon-? and Common ? Chain Cytokine Receptors to Reverse Autoimmune Diabetes in NOD Mice.

Publications

The JAK1 Selective Inhibitor ABT 317 Blocks Signaling Through Interferon-γ and Common γ Chain Cytokine Receptors to Reverse Autoimmune Diabetes in NOD Mice.

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