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Mechanisms and consequences of Jak–STAT signaling in the immune system

Nature Immunology volume 18, pages 374–384 (2017)Cite this article

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Abstract

Kinases of the Jak ('Janus kinase') family and transcription factors (TFs) of the STAT ('signal transducer and activator of transcription') family constitute a rapid membrane-to-nucleus signaling module that affects every aspect of the mammalian immune system. Research on this paradigmatic pathway has experienced breakneck growth in the quarter century since its discovery and has yielded a stream of basic and clinical insights that have profoundly influenced modern understanding of human health and disease, exemplified by the bench-to-bedside success of Jak inhibitors ('jakinibs') and pathway-targeting drugs. Here we review recent advances in Jak–STAT biology, focusing on immune cell function, disease etiology and therapeutic intervention, as well as broader principles of gene regulation and signal-dependent TFs.

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Figure 1: The canonical Jak–STAT pathway.
Figure 2: STATs as TFs.
Figure 3: 'Fine-tuning' Jak–STAT signaling.
Figure 4: Therapeutic targeting of the Jak–STAT pathway.

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References

  1. Stark, G.R. & Darnell, J.E. Jr. The JAK-STAT pathway at twenty. Immunity 36, 503–514 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Darnell, J.E. Jr., Kerr, I.M. & Stark, G.R. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 264, 1415–1421 (1994).

    Article  CAS  PubMed  Google Scholar 

  3. Levy, D.E. & Darnell, J.E. Jr. Signalling: Stats: transcriptional control and biological impact. Nat. Rev. Mol. Cell Biol. 3, 651–662 (2002).

    Article  CAS  PubMed  Google Scholar 

  4. Leonard, W.J. & O'Shea, J.J. JAKS and STATS: biological implications. Annu. Rev. Immunol. 16, 293–322 (1998).

    Article  CAS  PubMed  Google Scholar 

  5. Macchi, P. et al. Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID). Nature 377, 65–68 (1995).

    Article  CAS  PubMed  Google Scholar 

  6. Russell, S.M. et al. Mutation of Jak3 in a patient with SCID: essential role of Jak3 in lymphoid development. Science 270, 797–800 (1995).

    Article  CAS  PubMed  Google Scholar 

  7. Luo, H., Hanratty, W.P. & Dearolf, C.R. An amino acid substitution in the Drosophila hopTum-l Jak kinase causes leukemia-like hematopoietic defects. EMBO J. 14, 1412–1420 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Kralovics, R. et al.A gain-of-function mutation of JAK2 in myeloproliferative disorders. N. Engl. J. Med. 352, 1779–1790 (2005).

    Article  CAS  PubMed  Google Scholar 

  9. James, C. et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 434, 1144–1148 (2005).

    Article  CAS  PubMed  Google Scholar 

  10. Baxter, E.J. et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 365, 1054–1061 (2005).

    Article  CAS  PubMed  Google Scholar 

  11. Geyer, H.L. & Mesa, R.A. Therapy for myeloproliferative neoplasms: when, which agent, and how? Blood 124, 3529–3537 (2014).

    Article  CAS  PubMed  Google Scholar 

  12. Various. Ruxolitinib clinical trials (US). ClinicalTrials.gov. https://clinicaltrials.gov/ct2/results?term=&recr=&type=&rslt=&age_v=&gndr=&cond=&intr=Ruxolitinib (2016; accessed 2 December 2016).

  13. O'Shea, J.J. et al. The JAK-STAT pathway: impact on human disease and therapeutic intervention. Annu. Rev. Med. 66, 311–328 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Various. Tofacitinib clinical trials (US). ClinicalTrials.gov. https://clinicaltrials.gov/ct2/results?term=&recr=&type=&rslt=&age_v=&gndr=&cond=&intr=tofacitinib(2016; accessed 21 December 2016).

  15. Various. Jak inhibitor clinical trials (US). ClinicalTrials.gov. https://clinicaltrials.gov/ct2/results?term=JAK1+OR+JAK2+OR+JAK3+OR+TYK2+NOT+Tofacitinib+NOT+Ruxolitinib (2016; accessed 21 December 2016).

  16. Ghoreschi, K., Laurence, A. & O'Shea, J.J. Selectivity and therapeutic inhibition of kinases: to be or not to be? Nat. Immunol. 10, 356–360 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Tasian, S.K. et al. Potent efficacy of combined PI3K/mTOR and JAK or ABL inhibition in murine xenograft models of Ph-like acute lymphoblastic leukemia. Blood 129, 177–187 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Gao, S.P. et al. JAK2 inhibition sensitizes resistant EGFR-mutant lung adenocarcinoma to tyrosine kinase inhibitors. Sci. Signal. 9, ra33 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Britschgi, A. et al. JAK2/STAT5 inhibition circumvents resistance to PI3K/mTOR blockade: a rationale for cotargeting these pathways in metastatic breast cancer. Cancer Cell 22, 796–811 (2012).

    Article  CAS  PubMed  Google Scholar 

  20. Smith, G.A., Uchida, K., Weiss, A. & Taunton, J. essential biphasic role for JaK3 catalytic activity in IL-2 receptor signaling. Nat. Chem. Biol. 12, 373–379 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ross, S.H. et al. Phosphoproteomic Analyses of interleukin 2 signaling reveal integrated JAK kinase-dependent and -independent networks in CD8+ T cells. Immunity 45, 685–700 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Vahedi, G. et al. Super-enhancers delineate disease-associated regulatory nodes in T cells. Nature 520, 558–562 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Moodley, D. et al. Network pharmacology of JAK inhibitors. Proc. Natl. Acad. Sci. USA 113, 9852–9857 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Mostafavi, S. et al. Parsing the interferon transcriptional network and its disease associations. Cell 164, 564–578 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Koppikar, P. et al. Heterodimeric JAK-STAT activation as a mechanism of persistence to JAK2 inhibitor therapy. Nature 489, 155–159 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Springuel, L. et al. Cooperating JAK1 and JAK3 mutants increase resistance to JAK inhibitors. Blood 124, 3924–3931 (2014).

    Article  CAS  PubMed  Google Scholar 

  27. Benci, J.L. et al. Tumor interferon signaling regulates a multigenic resistance program to immune checkpoint blockade. Cell 167, 1540–1554 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Spangler, J.B., Moraga, I., Mendoza, J.L. & Garcia, K.C. Insights into cytokine-receptor interactions from cytokine engineering. Annu. Rev. Immunol. 33, 139–167 (2015).

    Article  CAS  PubMed  Google Scholar 

  29. Blouin, C.M. et al. Glycosylation-Dependent IFN-γR partitioning in lipid and actin nanodomains is critical for JAK activation. Cell 166, 920–934 (2016).

    Article  CAS  PubMed  Google Scholar 

  30. Ferrao, R. et al. The structural basis for class II cytokine receptor recognition by JAK1. Structure 24, 897–905 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Floss, D.M. et al. Defining the functional binding sites of interleukin 12 receptor β1 and interleukin 23 receptor to Janus kinases. Mol. Biol. Cell 27, 2301–2316 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Lupardus, P.J. et al. Structural snapshots of full-length Jak1, a transmembrane gp130/IL-6/IL-6Rα cytokine receptor complex, and the receptor-Jak1 holocomplex. Structure 19, 45–55 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wallweber, H.J.A., Tam, C., Franke, Y., Starovasnik, M.A. & Lupardus, P.J. Structural basis of recognition of interferon-α receptor by tyrosine kinase 2. Nat. Struct. Mol. Biol. 21, 443–448 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Zhang, D., Wlodawer, A. & Lubkowski, J. Crystal structure of a complex of the intracellular domain of interferon λ Receptor 1 (IFNLR1) and the FERM/SH2 domains of human JAK1. J. Mol. Biol. 428, 4651–4668 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Brooks, A.J. et al. Mechanism of activation of protein kinase JAK2 by the growth hormone receptor. Science 344, 1249783 (2014).

    Article  PubMed  CAS  Google Scholar 

  36. Ungureanu, D. et al. The pseudokinase domain of JAK2 is a dual-specificity protein kinase that negatively regulates cytokine signaling. Nat. Struct. Mol. Biol. 18, 971–976 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Bandaranayake, R.M. et al. Crystal structures of the JAK2 pseudokinase domain and the pathogenic mutant V617F. Nat. Struct. Mol. Biol. 19, 754–759 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Toms, A.V. et al. Structure of a pseudokinase-domain switch that controls oncogenic activation of Jak kinases. Nat. Struct. Mol. Biol. 20, 1221–1223 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Shan, Y. et al. Molecular basis for pseudokinase-dependent autoinhibition of JAK2 tyrosine kinase. Nat. Struct. Mol. Biol. 21, 579–584 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Wang, Y. & Levy, D.E. Comparative evolutionary genomics of the STAT family of transcription factors. JAK-STAT 1, 23–33 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Chen, X. et al. A reinterpretation of the dimerization interface of the N-terminal domains of STATs. Protein Sci. 12, 361–365 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Mao, X. et al. Structural bases of unphosphorylated STAT1 association and receptor binding. Mol. Cell 17, 761–771 (2005).

    Article  CAS  PubMed  Google Scholar 

  43. Neculai, D. et al. Structure of the unphosphorylated STAT5a dimer. J. Biol. Chem. 280, 40782–40787 (2005).

    Article  CAS  PubMed  Google Scholar 

  44. Li, J. et al. Structural basis for DNA recognition by STAT6. Proc. Natl. Acad. Sci. USA 113, 13015–13020 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Decker, T., Kovarik, P. & Meinke, A. GAS elements: a few nucleotides with a major impact on cytokine-induced gene expression. J. Interferon Cytokine Res. 17, 121–134 (1997).

    Article  CAS  PubMed  Google Scholar 

  46. Robertson, G. et al. Genome-wide profiles of STAT1 DNA association using chromatin immunoprecipitation and massively parallel sequencing. Nat. Methods 4, 651–657 (2007).

    Article  CAS  PubMed  Google Scholar 

  47. Shlyueva, D., Stampfel, G. & Stark, A. Transcriptional enhancers: from properties to genome-wide predictions. Nat. Rev. Genet. 15, 272–286 (2014).

    Article  CAS  PubMed  Google Scholar 

  48. Vahedi, G. et al. STATs shape the active enhancer landscape of T cell populations. Cell 151, 981–993 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Ostuni, R. et al. Latent Enhancers activated by stimulation in differentiated cells. Cell 152, 157–171 (2013).

    Article  CAS  PubMed  Google Scholar 

  50. Qiao, Y. et al. Synergistic activation of inflammatory cytokine genes by interferon-gamma-induced chromatin remodeling and Toll-like receptor signaling. Immunity 39, 454–469 (2013).

    Article  CAS  PubMed  Google Scholar 

  51. Wilson, C.B., Rowell, E. & Sekimata, M. Epigenetic control of T-helper-cell differentiation. Nat. Rev. Immunol. 9, 91–105 (2009).

    Article  CAS  PubMed  Google Scholar 

  52. Wei, L. et al. Discrete Roles of STAT4 and SwTAT6 transcription factors in tuning epigenetic modifications and transcription during T helper cell differentiation. Immunity 32, 840–851 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Durant, L. et al. Diverse targets of the transcription factor STAT3 contribute to T cell pathogenicity and homeostasis. Immunity 32, 605–615 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Qiao, Y., Kang, K., Giannopoulou, E., Fang, C. & Ivashkiv, L.B. IFN-γ induces histone 3 lysine 27 trimethylation in a small subset of promoters to stably silence gene expression in human macrophages. Cell Rep. 16, 3121–3129 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Kang, K., Yamaji, D., Yoo, K.H., Robinson, G.W. & Hennighausen, L. Mammary-specific gene activation is defined by progressive recruitment of stat5 during pregnancy and the establishment of H3K4me3 marks. Mol. Cell. Biol. 34, 464–473 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Willi, M., Yoo, K.H., Wang, C., Trajanoski, Z. & Hennighausen, L. Differential cytokine sensitivities of STAT5-dependent enhancers rely on Stat5 autoregulation. Nucleic Acids Res. 44, 10277–10291 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Bhattacharya, S. et al. Cooperation of Stat2 and p300/CBP in signalling induced by interferon-α. Nature 383, 344–347 (1996).

    Article  CAS  PubMed  Google Scholar 

  58. Mandal, M. et al. Epigenetic repression of the Igk locus by STAT5-mediated recruitment of the histone methyltransferase Ezh2. Nat. Immunol. 12, 1212–1220 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Veals, S.A. et al. Subunit of an alpha-interferon-responsive transcription factor is related to interferon regulatory factor and Myb families of DNA-binding proteins. Mol. Cell. Biol. 12, 3315–3324 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Schaefer, T.S., Sanders, L.K. & Nathans, D. Cooperative transcriptional activity of Jun and Stat3β, a short form of Stat3. Proc. Natl. Acad. Sci. USA 92, 9097–9101 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Stöcklin, E., Wissler, M., Gouilleux, F. & Groner, B. Functional interactions between Stat5 and the glucocorticoid receptor. Nature 383, 726–728 (1996).

    Article  PubMed  Google Scholar 

  62. Farlik, M. et al. Nonconventional initiation complex assembly by STAT and NF-kB transcription factors regulates nitric oxide synthase expression. Immunity 33, 25–34 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Chen, X. et al. Integration of external signaling pathways with the core transcriptional network in embryonic stem cells. Cell 133, 1106–1117 (2008).

    Article  CAS  PubMed  Google Scholar 

  64. Ciofani, M. et al. A validated regulatory network for Th17 cell specification. Cell 151, 289–303 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Li, P. et al. BATF-JUN is critical for IRF4-mediated transcription in T cells. Nature 490, 543–546 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Garber, M. et al. A high-throughput chromatin immunoprecipitation approach reveals principles of dynamic gene regulation in mammals. Mol. Cell 47, 810–822 (2012).

    Article  CAS  PubMed  Google Scholar 

  67. Langlais, D., Barreiro, L.B. & Gros, P. The macrophage IRF8/IRF1 regulome is required for protection against infections and is associated with chronic inflammation. J. Exp. Med. 213, 585–603 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Hossain, D.M.S. et al. FoxP3 acts as a cotranscription factor with STAT3 in tumor-induced regulatory T cells. Immunity 39, 1057–1069 (2013).

    Article  CAS  PubMed  Google Scholar 

  69. Kwon, H. et al. analysis of interleukin-21-induced Prdm1 gene regulation reveals functional cooperation of STAT3 and IRF4 transcription factors. Immunity 31, 941–952 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Xu, X., Sun, Y.L. & Hoey, T. Cooperative DNA binding and sequence-selective recognition conferred by the STAT amino-terminal domain. Science 273, 794–797 (1996).

    Article  CAS  PubMed  Google Scholar 

  71. John, S., Vinkemeier, U., Soldaini, E., Darnell, J.E. Jr. & Leonard, W.J. The significance of tetramerization in promoter recruitment by Stat5. Mol. Cell. Biol. 19, 1910–1918 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Shin, H.Y. et al. Hierarchy within the mammary STAT5-driven Wap super-enhancer. Nat. Genet. 48, 904–911 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Kang, K., Robinson, G.W. & Hennighausen, L. Comprehensive meta-analysis of signal transducers and activators of transcription (STAT) genomic binding patterns discerns cell-specific cis-regulatory modules. BMC Genomics 14, 4 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. O'Sullivan, A., Chang, H.C., Yu, Q. & Kaplan, M.H. STAT4 is required for interleukin-12-induced chromatin remodeling of the CD25 locus. J. Biol. Chem. 279, 7339–7345 (2004).

    Article  CAS  PubMed  Google Scholar 

  75. Akaishi, H. et al. Defective IL-2-mediated IL-2 receptor α chain expression in Stat3-deficient T lymphocytes. Int. Immunol. 10, 1747–1751 (1998).

    Article  CAS  PubMed  Google Scholar 

  76. Nakajima, H. et al. An indirect effect of Stat5a in IL-2-induced proliferation: a critical role for Stat5a in IL-2-mediated IL-2 receptor alpha chain induction. Immunity 7, 691–701 (1997).

    Article  CAS  PubMed  Google Scholar 

  77. Villarino, A.V. et al. Helper T cell IL-2 production is limited by negative feedback and STAT-dependent cytokine signals. J. Exp. Med. 204, 65–71 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Johnston, R.J., Choi, Y.S., Diamond, J.A., Yang, J.A. & Crotty, S. STAT5 is a potent negative regulator of TFH cell differentiation. J. Exp. Med. 209, 243–250 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Neumann, C. et al. Role of Blimp-1 in programing Th effector cells into IL-10 producers. J. Exp. Med. 211, 1807–1819 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Poholek, A.C. et al. IL-10 induces a STAT3-dependent autoregulatory loop in TH2 cells that promotes Blimp-1 restriction of cell expansion via antagonism of STAT5 target genes. Science Immunol. http://dx.doi.org/110.1126/sciimmunol.aaf8612 (2016).

  81. Langlais, D., Couture, C., Balsalobre, A. & Drouin, J. The Stat3/GR interaction code: predictive value of direct/indirect DNA recruitment for transcription outcome. Mol. Cell 47, 38–49 (2012).

    Article  CAS  PubMed  Google Scholar 

  82. Russell, B. in Dear Bertrand Russell: A Selection of His Correspondence with the General Public, 1950–1968 (eds. Feinberg, B. Kasrils, D.) 41‐42 Allen & Unwin, London, 1969).

    Google Scholar 

  83. Seidel, H.M. et al. Spacing of palindromic half sites as a determinant of selective STAT (signal transducers and activators of transcription) DNA binding and transcriptional activity. Proc. Nawtl. Acad. Sci. USA 92, 3041–3045 (1995).

    Article  CAS  Google Scholar 

  84. Schindler, U., Wu, P., Rothe, M., Brasseur, M. & McKnight, S.L. Components of a Stat recognition code: evidence for two layers of molecular selectivity. Immunity 2, 689–697 (1995).

    Article  CAS  PubMed  Google Scholar 

  85. Costa-Pereira, A.P. et al. Mutational switch of an IL-6 response to an interferon-γ-like response. Proc. Natl. Acad. Sci. USA 99, 8043–8047 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Qing, Y. & Stark, G.R. Alternative activation of STAT1 and STAT3 in response to interferon-γ. J. Biol. Chem. 279, 41679–41685 (2004).

    Article  CAS  PubMed  Google Scholar 

  87. Park, J.-H. et al. Signaling by intrathymic cytokines, not T cell antigen receptors, specifies CD8 lineage choice and promotes the differentiation of cytotoxic-lineage T cells. Nat. Immunol. 11, 257–264 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Yang, X.-P. et al. Opposing regulation of the locus encoding IL-17 through direct, reciprocal actions of STAT3 and STAT5. Nat. Immunol. 12, 247–254 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Zielinski, C.E. et al. Pathogen-induced human TH17 cells produce IFN-(or IL-10 and are regulated by IL-1β. Nature 484, 514–518 (2012).

    Article  CAS  PubMed  Google Scholar 

  90. Wan, C.-K. et al. The cytokines IL-21 and GM-CSF have opposing regulatory roles in the apoptosis of conventional dendritic cells. Immunity 38, 514–527 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Walker, S.R. et al. STAT5 outcompetes STAT3 To regulate the expression of the oncogenic transcriptional modulator BCL6. Mol. Cell. Biol. 33, 2879–2890 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Basu, R. et al. IL-1 signaling modulates activation of STAT transcription factors to antagonize retinoic acid signaling and control the TH17 cell-iTreg cell balance. Nat. Immunol. 16, 286–295 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Hirahara, K. et al. Asymmetric action of STAT transcription factors drives transcriptional outputs and cytokine specificity. Immunity 42, 877–889 (2015).

    Article  CAS  PubMed  Google Scholar 

  94. Jacobson, N.G. et al. Interleukin 12 signaling in T helper type 1 (Th1) cells involves tyrosine phosphorylation of signal transducer and activator of transcription (Stat)3 and Stat4. J. Exp. Med. 181, 1755–1762 (1995).

    Article  CAS  PubMed  Google Scholar 

  95. Lischke, A. et al. The interleukin-4 receptor activates STAT5 by a mechanism that relies upon common gamma-chain. J. Biol. Chem. 273, 31222–31229 (1998).

    Article  CAS  PubMed  Google Scholar 

  96. Nguyen, K.B. et al. Critical role for STAT4 activation by type 1 interferons in the interferon-γ response to viral infection. Science 297, 2063–2066 (2002).

    Article  CAS  PubMed  Google Scholar 

  97. Villarino, A.V. et al. The IL-27R (WSX-1) is required to suppress T cell hyperactivity during infection. Immunity 19, 645–655 (2003).

    Article  CAS  PubMed  Google Scholar 

  98. O'Shea, J.J. & Murray, P.J. Cytokine signaling modules in inflammatory responses. Immunity 28, 477–487 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Wan, C.-K. et al. Opposing roles of STAT1 and STAT3 in IL-21 function in CD4+ T cells. Proc. Natl. Acad. Sci. USA 112, 9394–9399 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Shuai, K. & Liu, B. Regulation of JAK-STAT signalling in the immune system. Nat. Rev. Immunol. 3, 900–911 (2003).

    Article  CAS  PubMed  Google Scholar 

  101. Bohmer, F.D. & Friedrich, K. Protein tyrosine phosphatases as wardens of STAT signaling. JAK-STAT 3, e28087 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  102. Lu, D. et al. The phosphatase DUSP2 controls the activity of the transcription activator STAT3 and regulates TH17 differentiation. Nat. Immunol. 16, 1263–1273 (2015).

    Article  CAS  PubMed  Google Scholar 

  103. Liu, B. et al. PIAS1 selectively inhibits interferon-inducible genes and is important in innate immunity. Nat. Immunol. 5, 891–898 (2004).

    Article  CAS  PubMed  Google Scholar 

  104. Liu, B., Tahk, S., Yee, K.M., Fan, G. & Shuai, K. The ligase PIAS1 restricts natural regulatory T cell differentiation by epigenetic repression. Science 330, 521–525 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Yoshimura, A., Naka, T. & Kubo, M. SOCS proteins, cytokine signalling and immune regulation. Nat. Rev. Immunol. 7, 454–465 (2007).

    Article  CAS  PubMed  Google Scholar 

  106. Kershaw, N.J. et al. SOCS3 binds specific receptor-JAK complexes to control cytokine signaling by direct kinase inhibition. Nat. Struct. Mol. Biol. 20, 469–476 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Croker, B.A. et al. SOCS3 negatively regulates IL-6 signaling in vivo. Nat. Immunol. 4, 540–545 (2003).

    Article  CAS  PubMed  Google Scholar 

  108. Lang, R. et al. SOCS3 regulates the plasticity of gp130 signaling. Nat. Immunol. 4, 546–550 (2003).

    Article  CAS  PubMed  Google Scholar 

  109. Yang, X.O. et al. The signaling suppressor CIS controls proallergic T cell development and allergic airway inflammation. Nat. Immunol. 14, 732–740 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Takahashi, R. et al. SOCS1 is essential for regulatory T cell functions by preventing loss of Foxp3 expression as well as IFN- and IL-17A production. J. Exp. Med. 208, 2055–2067 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Luckey, M.A. et al. The transcription factor ThPOK suppresses Runx3 and imposes CD4+ lineage fate by inducing the SOCS suppressors of cytokine signaling. Nat. Immunol. 15, 638–645 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Spence, S. et al. Suppressors of cytokine signaling 2 and 3 diametrically control macrophage polarization. Immunity 38, 66–78 (2012).

    Article  PubMed  CAS  Google Scholar 

  113. Pellegrini, M. et al. IL-7 engages multiple mechanisms to overcome chronic viral infection and limit organ pathology. Cell 144, 601–613 (2011).

    Article  CAS  PubMed  Google Scholar 

  114. Delconte, R.B. et al. The helix-loop-helix protein ID2 governs NK cell fate by tuning their sensitivity to interleukin-15. Immunity 44, 103–115 (2016).

    Article  CAS  PubMed  Google Scholar 

  115. Miyagi, T. et al. High basal STAT4 balanced by STAT1 induction to control type 1 interferon effects in natural killer cells. J. Exp. Med. 204, 2383–2396 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Gil, M.P. et al. Regulating type 1 IFN effects in CD8 T cells during viral infections: changing STAT4 and STAT1 expression for function. Blood 120, 3718–3728 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Villarino, A.V. et al. Signal transducer and activator of transcription 5 (STAT5) paralog dose governs T cell effector and regulatory functions. eLife http://dx.doi.org/10.7554/eLife.08384 (2016).

  118. Usui, T., Nishikomori, R., Kitani, A. & Strober, W. GATA-3 suppresses Th1 development by downregulation of Stat4 and not through effects on IL-12Rβ2 chain or T-bet. Immunity 18, 415–428 (2003).

    Article  CAS  PubMed  Google Scholar 

  119. Cheon, H., Yang, J. & Stark, G.R. The functions of signal transducers and activators of transcriptions 1 and 3 as cytokine-inducible proteins. J. Interferon Cytokine Res. 31, 33–40 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Metser, G. et al. An autoregulatory enhancer controls mammary-specific STAT5 functions. Nucleic Acids Res. 44, 1052–1063 (2016).

    Article  CAS  PubMed  Google Scholar 

  121. Witte, S. & Muljo, S.A. Integrating non-coding RNAs in JAK-STAT regulatory networks. JAK-STAT 3, e28055 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  122. Kim, T.K. & Maniatis, T. Regulation of interferon-gamma-activated STAT1 by the ubiquitin-proteasome pathway. Science 273, 1717–1719 (1996).

    Article  CAS  PubMed  Google Scholar 

  123. Tanaka, T., Soriano, M.A. & Grusby, M.J. SLIM is a nuclear ubiquitin E3 ligase that negatively regulates STAT signaling. Immunity 22, 729–736 (2005).

    Article  CAS  PubMed  Google Scholar 

  124. Tanaka, T. et al. PDLIM2 inhibits T helper 17 cell development and granulomatous inflammation through degradation of STAT3. Sci. Signal. 4, ra85 (2011).

    Article  PubMed  CAS  Google Scholar 

  125. Sahoo, A., Alekseev, A., Obertas, L. & Nurieva, R. Grail controls Th2 cell development by targeting STAT6 for degradation. Nat. Commun. 5, 4732 (2014).

    Article  CAS  PubMed  Google Scholar 

  126. Villarino, A.V., Kanno, Y., Ferdinand, J.R. & O'Shea, J.J. Mechanisms of Jak/STAT signaling in immunity and disease. J. Immunol. 194, 21–27 (2015).

    Article  CAS  PubMed  Google Scholar 

  127. Delgoffe, G.M. & Vignali, D.A. STAT heterodimers in immunity. JAK-STAT 2, e23060 (2014).

    Article  Google Scholar 

  128. Vinkemeier, U., Moarefi, I., Darnell, J.E. Jr. & Kuriyan, J. Structure of the amino-terminal protein interaction domain of STAT-4. Science 279, 1048–1052 (1998).

    Article  CAS  PubMed  Google Scholar 

  129. Begitt, A. et al. STAT1-cooperative DNA binding distinguishes type 1 from type 2 interferon signaling. Nat. Immunol. 15, 168–176 (2014).

    Article  CAS  PubMed  Google Scholar 

  130. Lin, J.-X. et al. Critical role of STAT5 transcription factor tetramerization for cytokine responses and normal immune function. Immunity 36, 586–599 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Yang, J. et al. Unphosphorylated STAT3 accumulates in response to IL-6 and activates transcription by binding to NFkappaB. Genes Dev. 21, 1396–1408 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Cheon, H. & Stark, G.R. Unphosphorylated STAT1 prolongs the expression of interferon-induced immune regulatory genes. Proc. Natl. Acad. Sci. USA 106, 9373–9378 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Park, H.J. et al. Cytokine-induced megakaryocytic differentiation is regulated by genome-wide loss of a uSTAT transcriptional program. EMBO J. 35, 580–594 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  134. Carbognin, E., Betto, R.M., Soriano, M.E., Smith, A.G. & Martello, G. Stat3 promotes mitochondrial transcription and oxidative respiration during maintenance and induction of naive pluripotency. EMBO J. 35, 618–634 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Putz, E.M. et al. CDK8-mediated STAT1–S727 phosphorylation restrains NK cell cytotoxicity and tumor surveillance. Cell Rep. 4, 437–444 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Bancerek, J. et al. CDK8 kinase phosphorylates transcription factor STAT1 to selectively regulate the interferon response. Immunity 10.1016/j.immuni. 38, 250–262 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Begitt, A., Droescher, M., Knobeloch, K.P. & Vinkemeier, U. SUMO conjugation of STAT1 protects cells from hyperresponsiveness to IFN. Blood 118, 1002–1007 (2011).

    Article  CAS  PubMed  Google Scholar 

  138. Wegrzyn, J. et al. Function of mitochondrial Stat3 in cellular respiration. Science 323, 793–797 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Gough, D.J. et al. Mitochondrial STAT3 supports Ras-Dependent oncogenic transformation. Science 324, 1713–1716 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Friedbichler, K. et al. Stat5a serine 725 and 779 phosphorylation is a prerequisite for hematopoietic transformation. Blood 116, 1548–1558 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Gough, D.J., Marié, I.J., Lobry, C., Aifantis, I. & Levy, D.E. STAT3 supports experimental K-RasG12D-induced murine myeloproliferative neoplasms dependent on serine phosphorylation. Blood 124, 2252–2261 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Dasgupta, M., Dermawan, J.K.T., Willard, B. & Stark, G.R. STAT3-driven transcription depends upon the dimethylation of K49 by EZH2. Proc. Natl. Acad. Sci. USA 112, 3985–3990 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Beier, U.H. et al. Histone deacetylases 6 and 9 and sirtuin-1 control Foxp3+ regulatory T cell function through shared and isoform-specific mechanisms. Sci. Signal. 5, ra45 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  144. Yarilina, A., Park-Min, K.-H., Antoniv, T., Hu, X. & Ivashkiv, L.B. TNF activates an IRF1-dependent autocrine loop leading to sustained expression of chemokines and STAT1-dependent type I interferon–response genes. Nat. Immunol. 9, 378–387 (2008).

    Article  CAS  PubMed  Google Scholar 

  145. Ivashkiv, L.B. & Donlin, L.T. Regulation of type I interferon responses. Nat. Rev. Immunol. 14, 36–49 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Bezbradica, J.S., Rosenstein, R.K., Demarco, R.A., Brodsky, I. & Medzhitov, R. A role for the ITAM signaling module in specifying cytokine-receptor functions. Nat. Immunol. 15, 333–342 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Yi, Z., Lin, W.W., Stunz, L.L. & Bishop, G.A. The adaptor TRAF3 restrains the lineage determination of thymic regulatory T cells by modulating signaling via the receptor for IL-2. Nat. Immunol. 15, 866–874 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Nagashima, H. et al. The adaptor TRAF5 limits the differentiation of inflammatory CD4+ T cells by antagonizing signaling via the receptor for IL-6. Nat. Immunol. 15, 449–456 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Upton, C., Mossman, K. & McFadden, G. Encoding of a homolog of the IFN-γ receptor by myxoma virus. Science 258, 1369–1372 (1992).

    Article  CAS  PubMed  Google Scholar 

  150. Guan, K.L., Broyles, S.S. & Dixon, J.E.A. Tyr/Ser protein phosphatase encoded by vaccinia virus. Nature 350, 359–362 (1991).

    Article  CAS  PubMed  Google Scholar 

  151. Morrison, T.E., Mauser, A., Wong, A., Ting, J.P. & Kenney, S.C. Inhibition of IFN-γ signaling by an Epstein-Barr virus immediate-early protein. Immunity 15, 787–799 (2001).

    Article  CAS  PubMed  Google Scholar 

  152. Ong, Y.C., Reese, M.L. & Boothroyd, J.C. Toxoplasma rhoptry protein 16 (ROP16) subverts host function by direct tyrosine phosphorylation of STAT6. J. Biol. Chem. 285, 28731–28740 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Saeij, J.P.J. et al. Toxoplasma co-opts host gene expression by injection of a polymorphic kinase homologue. Nature 445, 324–327 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  154. Olias, P., Etheridge, R.D., Zhang, Y., Holtzman, M.J. & Sibley, L.D. Toxoplasma effector recruits the Mi-2/NuRD complex to repress STAT1 Transcription and block IFN-γ-dependent gene expression. Cell Host Microbe 20, 72–82 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Gay, G. et al. Toxoplasma gondii TgIST co-opts host chromatin repressors dampening STAT1-dependent gene regulation and IFN-γ-mediated host defenses. J. Exp. Med. 213, 1779–1798 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Casanova, J.L., Holland, S.M. & Notarangelo, L.D. Inborn errors of Human JAKs and STATs. Immunity 36, 515–528 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Kanai, T., Jenks, J. & Nadeau, K.C. The STAT5b pathway defect and autoimmunity. Front. Immunol. 3, 234 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  158. Boisson-Dupuis, S. et al. Inborn errors of human STAT1: allelic heterogeneity governs the diversity of immunological and infectious phenotypes. Curr. Opin. Immunol. 24, 364–378 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Chen, E., Staudt, L.M. & Green, A.R. Janus kinase deregulation in leukemia and lymphoma. Immunity 36, 529–541 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Robinson, D.R. et al. Identification of recurrent NAB2-STAT6 gene fusions in solitary fibrous tumor by integrative sequencing. Nat. Genet. 45, 180–185 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Chmielecki, J. et al. Whole-exome sequencing identifies a recurrent NAB2-STAT6 fusion in solitary fibrous tumors. Nat. Genet. 45, 131–132 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Dong, S. & Tweardy, D.J. Interactions of STAT5b-RARα, a novel acute promyelocytic leukemia fusion protein, with retinoic acid receptor and STAT3 signaling pathways. Blood 99, 2637–2646 (2002).

    Article  CAS  PubMed  Google Scholar 

  163. Pilati, C. et al. Somatic mutations activating STAT3 in human inflammatory hepatocellular adenomas. J. Exp. Med. 208, 1359–1366 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Koskela, H.L.M. et al. Somatic STAT3 mutations in large granular lymphocytic leukemia. N. Engl. J. Med. 366, 1905–1913 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Jerez, A. et al. STAT3 mutations unify the pathogenesis of chronic lymphoproliferative disorders of NK cells and T-cell large granular lymphocyte leukemia. Blood 120, 3048–3057 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Rajala, H.L.M. et al. Discovery of somatic STAT5b mutations in large granular lymphocytic leukemia. Blood 121, 4541–4550 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Yildiz, M. et al. Activating STAT6 mutations in follicular lymphoma. Blood 125, 668–679 (2014).

    Article  PubMed  CAS  Google Scholar 

  168. Kiel, M.J. et al. Genomic analyses reveal recurrent mutations in epigenetic modifiers and the JAK-STAT pathway in Sezary syndrome. Nat. Commun. 6, 8470 (2015).

    Article  CAS  PubMed  Google Scholar 

  169. Crescenzo, R. et al. Convergent mutations and kinase fusions lead to oncogenic STAT3 activation in anaplastic large cell lymphoma. Cancer Cell 27, 516–532 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Bettelli, E. et al. Loss of T-bet, but not STAT1, prevents the development of experimental autoimmune encephalomyelitis. J. Exp. Med. 200, 79–87 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Villarino, A.V., Gallo, E. & Abbas, A.K. STAT1-activating cytokines limit Th17 responses through both T-bet-dependent and -independent mechanisms. J. Immunol. 185, 6461–6471 (2010).

    Article  CAS  PubMed  Google Scholar 

  172. Takeda, K. et al. Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality. Proc. Natl. Acad. Sci. USA 94, 3801–3804 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Stritesky, G.L. et al. The transcription factor STAT3 is required for T helper 2 cell development. Immunity 34, 39–49 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Zhou, L. et al. IL-6 programs TH-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat. Immunol. 8, 967–974 (2007).

    Article  CAS  PubMed  Google Scholar 

  175. Ray, J.P. et al. Transcription factor STAT3 and type I interferons are corepressive insulators for differentiation of follicular helper and T helper 1 cells. Immunity 40, 367–377 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Cui, W., Liu, Y., Weinstein, J.S., Craft, J. & Kaech, S.M. An interleukin-21- interleukin-10-STAT3 pathway is critical for functional maturation of memory CD8+ T cells. Immunity 35, 792–805 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Guo, X. et al. Induction of innate lymphoid cell-derived interleukin-22 by the transcription factor STAT3 mediates protection against intestinal infection. Immunity 40, 25–39 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Laouar, Y., Welte, T., Fu, X.-Y. & Flavell, R.A. STAT3 is required for Flt3L-dependent dendritic cell differentiation. Immunity 19, 903–912 (2003).

    Article  CAS  PubMed  Google Scholar 

  179. Cheng, F. et al. A critical role for Stat3 signaling in immune tolerance. Immunity 19, 425–436 (2003).

    Article  CAS  PubMed  Google Scholar 

  180. Takeda, K. et al. Enhanced Th1 activity and development of chronic enterocolitis in mice devoid of Stat3 in macrophages and neutrophils. Immunity 10, 39–49 (1999).

    Article  CAS  PubMed  Google Scholar 

  181. Yao, Z. et al. Stat5a/b are essential for normal lymphoid development and differentiation. Proc. Natl. Acad. Sci. USA 103, 1000–1005 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Yao, Z. et al. Nonredundant roles for Stat5a/b in directly regulating Foxp3. Blood 109, 4368–4375 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Laurence, A. et al. Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity 26, 371–381 (2007).

    Article  CAS  PubMed  Google Scholar 

  184. Liao, W., Lin, J.-X., Wang, L., Li, P. & Leonard, W.J. Modulation of cytokine receptors by IL-2 broadly regulates differentiation into helper T cell lineages. Nat. Immunol. 12, 551–559 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Liao, W. et al. Priming for T helper type 2 differentiation by interleukin 2–mediated induction of interleukin 4 receptor α-chain expression. Nat. Immunol. 9, 1288–1296 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Eckelhart, E. et al. A novel Ncr1-Cre mouse reveals the essential role of STAT5 for NK-cell survival and development. Blood 117, 1565–1573 (2011).

    Article  CAS  PubMed  Google Scholar 

  187. Mitchell, D.M. & Williams, M.A. Disparate roles for STAT5 in primary and secondary CTL responses. J. Immunol. 190, 3390–3398 (2013).

    Article  CAS  PubMed  Google Scholar 

  188. Esashi, E. et al. The signal transducer STAT5 inhibits plasmacytoid dendritic cell development by suppressing transcription factor IRF8. Immunity 28, 509–520 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Bell, B.D. et al. The transcription factor STAT5 is critical in dendritic cells for the development of TH2 but not TH1 responses. Nat. Immunol. 14, 1–10 (2013).

    Article  CAS  Google Scholar 

  190. Tiedt, R. et al. Ratio of mutant JAK2–V617F to wild-type Jak2 determines the MPD phenotypes in transgenic mice. Blood 111, 3931–3940 (2008).

    Article  CAS  PubMed  Google Scholar 

  191. Steward-Tharp, S.M. et al. A mouse model of HIES reveals pro- and anti-inflammatory functions of STAT3. Blood 123, 2978–2987 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Ohtani, T. et al. Dissection of signaling cascades through gp130 in vivo. Immunity 12, 95–105 (2000).

    Article  CAS  PubMed  Google Scholar 

  193. Jenkins, B.J. et al. Hyperactivation of Stat3 in gp130 mutant mice promotes gastric hyperproliferation and desensitizes TGF-β signaling. Nat. Med. 11, 845–852 (2005).

    Article  CAS  PubMed  Google Scholar 

  194. Varinou, L. et al. Phosphorylation of the Stat1 transactivation domain is required for full-fledged IFN-gamma-dependent innate immunity. Immunity 19, 793–802 (2003).

    Article  CAS  PubMed  Google Scholar 

  195. Dixit, A. et al. Perturb-Seq: dissecting molecular circuits with scalable single-cell RNA profiling of pooled genetic screens. Cell 167, 1853–1857 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Jaitin, D.A. et al. Dissecting immune circuits by linking CRISPR-pooled screens with single-cell RNA-seq. Cell 167, 1883–1896 (2016).

    Article  CAS  PubMed  Google Scholar 

  197. O'Shea, J.J., Kanno, Y. & Chan, A.C. In search of magic bullets: the golden age of immunotherapeutics. Cell 157, 227–240 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Various. Recombinant IL-2, IL-7, IL-12 and IL-15 clinical trials (US). ClinicalTrials.gov. https://clinicaltrials.gov/ct2/results?term=&recr=&type=Intr&rslt=&age_v=&gndr=&cond=&intr=Recombinant+AND+IL-2+OR+IL-7+OR+IL-15+OR+IL-12 (2016).

  199. Arenas-Ramirez, N., Woytschak, J. & Boyman, O. Interleukin-2: biology, design and application. Trends Immunol. 36, 763–777 (2015).

    Article  CAS  PubMed  Google Scholar 

  200. Neri, D. & Sondel, P.M. ScienceDirectImmunocytokines for cancer treatment: past, present and future. Autoimmunity 40, 96–102 (2016).

    CAS  Google Scholar 

  201. Lefranc, M.-P. Immunoglobulin and T cell receptor genes: IMGT® and the birth and rise of immunoinformatics. Front. Immunol. 5, 22 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  202. Toffalini, F. & Demoulin, J.-B. New insights into the mechanisms of hematopoietic cell transformation by activated receptor tyrosine kinases. Blood 116, 2429–2437 (2010).

    Article  CAS  PubMed  Google Scholar 

  203. Sen, M. & Grandis, J.R. Nucleic acid-based approaches to STAT inhibition. JAK-STAT 1, 285–291 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  204. Miklossy, G., Hilliard, T.S. & Turkson, J. Therapeutic modulators of STAT signalling for human diseases. Nat. Rev. Drug Discov. 12, 611–629 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Various. STAT inhibitor clinical trials (US). ClinicalTrials.gov. Available at: https://clinicaltrials.gov/ct2/results?term=&recr=&type=Intr&rslt=&age_v=&gndr=&cond=&intr=STAT3+OR+STAT5; accessed 21 December (2016).

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Acknowledgements

We thank members of the O'Shea laboratory for discussions about Jak–STAT biology, and C. Hunter and L. Hennighausen for critical reading of this manuscript. Supported by the National Institute of Arthritis, Musculoskeletal and Skin Diseases and the US National Institutes of Health (intramural funding).

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  1. Molecular Immunology and Inflammation Branch, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA

    Alejandro V Villarino, Yuka Kanno & John J O'Shea

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J.J.O. and the National Institutes of Health hold patents related to Jaks as targets of immunomodulatory agents and have a Collaborative Research Agreement and Development Award with Pfizer.

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Villarino, A., Kanno, Y. & O'Shea, J. Mechanisms and consequences of Jak–STAT signaling in the immune system. Nat Immunol 18, 374–384 (2017). https://doi.org/10.1038/ni.3691

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