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JAK and STAT Signaling Molecules in Immunoregulation and Immune-Mediated Disease

2012; Cell Press; Volume: 36; Issue: 4 Linguagem: Inglês

10.1016/j.immuni.2012.03.014

ISSN

1097-4180

Autores

John J. O’Shea, Robert Plenge,

Tópico(s)

Reproductive System and Pregnancy

Resumo

The discovery of the Janus kinase (JAK)-signal transducer and activator of transcripton (STAT) signaling pathway, a landmark in cell biology, provided a simple mechanism for gene regulation that dramatically advanced our understanding of the action of hormones, interferons, colony-stimulating factors, and interleukins. As we learn more about the complexities of immune responses, new insights into the functions of this pathway continue to be revealed, aided by technology that permits genome-wide views. As we celebrate the 20th anniversary of the discovery of this paradigm in cell signaling, it is particularly edifying to see how this knowledge has rapidly been translated to human immune disease. Not only have genome-wide association studies demonstrated that this pathway is highly relevant to human autoimmunity, but targeting JAKs is now a reality in immune-mediated disease. The discovery of the Janus kinase (JAK)-signal transducer and activator of transcripton (STAT) signaling pathway, a landmark in cell biology, provided a simple mechanism for gene regulation that dramatically advanced our understanding of the action of hormones, interferons, colony-stimulating factors, and interleukins. As we learn more about the complexities of immune responses, new insights into the functions of this pathway continue to be revealed, aided by technology that permits genome-wide views. As we celebrate the 20th anniversary of the discovery of this paradigm in cell signaling, it is particularly edifying to see how this knowledge has rapidly been translated to human immune disease. Not only have genome-wide association studies demonstrated that this pathway is highly relevant to human autoimmunity, but targeting JAKs is now a reality in immune-mediated disease. The importance of interferons (IFNs) and hormones such as erythropoietin, growth hormone, and prolactin has been recognized for more than half a century. With the advent of the molecular biology era came the discovery of a plethora of other cytokines, which we now know regulate all aspects of cell development and differentiation. Cytokines represent a collection of structurally distinct ligands that bind to different classes of receptors. A major subgroup of cytokines, comprising roughly 60 factors, bind to receptors termed type I and type II cytokine receptors. Cytokines that bind these receptors include type I IFNs, IFN-γ, many interleukins, and colony-stimulating factors. From an immunology perspective, these cytokines are important for initiating innate immunity, orchestrating adaptive immune mechanisms, and constraining immune and inflammatory responses. As discussed by Stark and Darnell, 2012Stark G.R. Darnell J.E. The JAK-STAT pathway at twenty.Immunity. 2012; 36 (this issue): 503-514Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar in this issue, the discovery of Janus kinases and of signal transducers and activators of transcription (JAKs and STATs) stemmed from attempts to understand how IFNs exerted their effect. However, we now know that all type I and II cytokine receptors selectively associate with JAKs (JAK1, JAK2, JAK3, or TYK2). For these receptors, activation of the receptor-bound JAKs is critical for initiating phosphorylation of the cytokine receptor and subsequent recruitment of one or more STATs. Over the past two decades, multiple lines of evidence have clearly established the roles of different JAKs and STATs in mediating the effect of cytokines that use type I and type II cytokine receptors in immunoregulation, host defense, and immunopathology (Darnell et al., 1994Darnell Jr., J.E. Kerr I.M. Stark G.R. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins.Science. 1994; 264: 1415-1421Crossref PubMed Google Scholar, Leonard and O'Shea, 1998Leonard W.J. O'Shea J.J. Jaks and STATs: biological implications.Annu. Rev. Immunol. 1998; 16: 293-322Crossref PubMed Scopus (1019) Google Scholar, O'Shea and Murray, 2008O'Shea J.J. Murray P.J. Cytokine signaling modules in inflammatory responses.Immunity. 2008; 28: 477-487Abstract Full Text Full Text PDF PubMed Scopus (229) Google Scholar). As our understanding of these processes have become more sophisticated, additional roles for this signaling pathway have been recognized. For instance, with the identification of “newer” T helper (Th) cell subsets comes the appreciation of important roles of STATs in these subsets as well as unexpected roles for STATs in recognized subsets. As our understanding of the mechanisms involved in innate immunity expands, previously unrecognized roles of STATs in these processes become evident. In addition, new technologies also allow comprehensive views of STAT action whereas insights from genome-wide association studies clearly implicate JAKs and STATs in human autoimmunity. Finally, the possibility of targeting the JAK-STAT pathway in autoimmune disease has now become a reality. When the STATs were first discovered, the palette of helper T cells was simple: Th1 and Th2 cells. TYK2, JAK2, and STAT4 were found to be critical for interleukin-12 (IL-12) signals and Th1 cell differentiation whereas JAK1, JAK3, and STAT6 were key for IL-4 signaling (Darnell et al., 1994Darnell Jr., J.E. Kerr I.M. Stark G.R. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins.Science. 1994; 264: 1415-1421Crossref PubMed Google Scholar, Leonard and O'Shea, 1998Leonard W.J. O'Shea J.J. Jaks and STATs: biological implications.Annu. Rev. Immunol. 1998; 16: 293-322Crossref PubMed Scopus (1019) Google Scholar, O'Shea and Murray, 2008O'Shea J.J. Murray P.J. Cytokine signaling modules in inflammatory responses.Immunity. 2008; 28: 477-487Abstract Full Text Full Text PDF PubMed Scopus (229) Google Scholar). In various models of infectious disease and immune-mediated disease, deficiency of STAT4 and STAT6 had the expected outcomes. It is now appreciated, however, that Th2 cell responses can occur in the absence of STAT6 (van Panhuys et al., 2008van Panhuys N. Tang S.C. Prout M. Camberis M. Scarlett D. Roberts J. Hu-Li J. Paul W.E. Le Gros G. In vivo studies fail to reveal a role for IL-4 or STAT6 signaling in Th2 lymphocyte differentiation.Proc. Natl. Acad. Sci. USA. 2008; 105: 12423-12428Crossref PubMed Scopus (51) Google Scholar). In fact, early Th2 cell differentiation can by driven by IL-2, which upregulates the transcription factor GATA3 and enhances IL-4 receptor expression (Paul, 2010Paul W.E. What determines Th2 differentiation, in vitro and in vivo?.Immunol. Cell Biol. 2010; 88: 236-239Crossref PubMed Scopus (28) Google Scholar). Activated by IL-2, STAT5A and STAT5B can directly bind the Il4ra gene and promote its expression (Liao et al., 2008Liao W. Schones D.E. Oh J. Cui Y. Cui K. Roh T.Y. Zhao K. Leonard W.J. Priming for T helper type 2 differentiation by interleukin 2-mediated induction of interleukin 4 receptor alpha-chain expression.Nat. Immunol. 2008; 9: 1288-1296Crossref PubMed Scopus (76) Google Scholar); however, STAT5A and STAT5B can also enhance Th1 cell responses by regulating Tbx21 and Il12rb2 (Liao et al., 2011bLiao 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. 2011; 12: 551-559Crossref PubMed Scopus (67) Google Scholar). Interestingly, STAT3 is also a contributor to Th2 cell differentiation and binds Th2 cell-associated gene loci (Liao et al., 2008Liao W. Schones D.E. Oh J. Cui Y. Cui K. Roh T.Y. Zhao K. Leonard W.J. Priming for T helper type 2 differentiation by interleukin 2-mediated induction of interleukin 4 receptor alpha-chain expression.Nat. Immunol. 2008; 9: 1288-1296Crossref PubMed Scopus (76) Google Scholar, Stritesky et al., 2011Stritesky G.L. Muthukrishnan R. Sehra S. Goswami R. Pham D. Travers J. Nguyen E.T. Levy D.E. Kaplan M.H. The transcription factor STAT3 is required for T helper 2 cell development.Immunity. 2011; 34: 39-49Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar). Thus, in contrast to the previous views equating STAT6 with Th2 cell differentiation, it appears that this process involves more subtle and complex interactions of STAT3, STAT5, and STAT6 with the relevant genetic loci. Along with the cytokine TGF-β, IL-2 is a key regulator of differentiation of regulatory T (Treg) cells in the thymus and the periphery. As mediators of IL-2 signaling, STAT5A and STAT5B are critical for the differentiation of Treg cells. Their effect is very direct in that STAT5A and STAT5B directly bind the Foxp3 gene and drive expression of this key gene (Yao et al., 2006Yao Z. Cui Y. Watford W.T. Bream J.H. Yamaoka K. Hissong B.D. Li D. Durum S.K. Jiang Q. Bhandoola A. et al.Stat5a/b are essential for normal lymphoid development and differentiation.Proc. Natl. Acad. Sci. USA. 2006; 103: 1000-1005Crossref PubMed Scopus (159) Google Scholar, Yao et al., 2007Yao Z. Kanno Y. Kerenyi M. Stephens G. Durant L. Watford W.T. Laurence A. Robinson G.W. Shevach E.M. Moriggl R. et al.Nonredundant roles for Stat5a/b in directly regulating Foxp3.Blood. 2007; 109: 4368-4375Crossref PubMed Scopus (215) Google Scholar, Zorn et al., 2006Zorn E. Nelson E.A. Mohseni M. Porcheray F. Kim H. Litsa D. Bellucci R. Raderschall E. Canning C. Soiffer R.J. et al.IL-2 regulates FOXP3 expression in human CD4+CD25+ regulatory T cells through a STAT-dependent mechanism and induces the expansion of these cells in vivo.Blood. 2006; 108: 1571-1579Crossref PubMed Scopus (285) Google Scholar). In addition, STAT5A and STAT5B regulate Il2ra, expression of which is also a critical for Treg cells. Surprisingly, STAT3 also has an important role in Treg cell function (Chaudhry et al., 2009Chaudhry A. Rudra D. Treuting P. Samstein R.M. Liang Y. Kas A. Rudensky A.Y. CD4+ regulatory T cells control TH17 responses in a Stat3-dependent manner.Science. 2009; 326: 986-991Crossref PubMed Scopus (271) Google Scholar). Deletion of STAT3 in Treg cells results in lethal gastrointestinal disease, but the effect is selective and does not globally impair Treg cell function. Treg cells retain the ability to limit T cell proliferation but have impaired ability to block Th17 cell-mediated pathology. Of interest, STAT3 physically associates with Foxp3. With the recognition of a multiplicity of fates for T cells, it has become clear that STATs are also key elements for these “new” subsets. We now know that STAT3 is critical for Th17 cell differentiation both in mouse and humans, mediating signals by IL-23 and IL-6 (Chen et al., 2006Chen Z. Laurence A. Kanno Y. Pacher-Zavisin M. Zhu B.M. Tato C. Yoshimura A. Hennighausen L. O'Shea J.J. Selective regulatory function of Socs3 in the formation of IL-17-secreting T cells.Proc. Natl. Acad. Sci. USA. 2006; 103: 8137-8142Crossref PubMed Scopus (304) Google Scholar, Milner et al., 2008Milner J.D. Brenchley J.M. Laurence A. Freeman A.F. Hill B.J. Elias K.M. Kanno Y. Spalding C. Elloumi H.Z. Paulson M.L. et al.Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome.Nature. 2008; 452: 773-776Crossref PubMed Scopus (424) Google Scholar). STAT3 regulates Th17 cell differentiation by directly binding Il17a and Il17f, Rorc, and Il23r, as well as other genes involved in Th17 cell differentiation (Durant et al., 2010Durant L. Watford W.T. Ramos H.L. Laurence A. Vahedi G. Wei L. Takahashi H. Sun H.W. Kanno Y. Powrie F. O'Shea J.J. Diverse targets of the transcription factor STAT3 contribute to T cell pathogenicity and homeostasis.Immunity. 2010; 32: 605-615Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar). Interestingly, IL-2, acting via STAT5A and STAT5B, is an important negative regulator of Th17 cell differentiation (Laurence et al., 2007Laurence A. Tato C.M. Davidson T.S. Kanno Y. Chen Z. Yao Z. Blank R.B. Meylan F. Siegel R. Hennighausen L. et al.Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation.Immunity. 2007; 26: 371-381Abstract Full Text Full Text PDF PubMed Scopus (555) Google Scholar). In this case, the actions of STAT5A and STAT5B are very direct as they compete with STAT3 binding to the Il17a-f locus (Yang et al., 2011Yang X.P. Ghoreschi K. Steward-Tharp S.M. Rodriguez-Canales J. Zhu J. Grainger J.R. Hirahara K. Sun H.W. Wei L. Vahedi G. et al.Opposing regulation of the locus encoding IL-17 through direct, reciprocal actions of STAT3 and STAT5.Nat. Immunol. 2011; 12: 247-254Crossref PubMed Scopus (131) Google Scholar). Intriguingly, by sequestering IL-2, regulatory T cells promote Th17 cell differentiation (Chen et al., 2011bChen Y. Haines C.J. Gutcher I. Hochweller K. Blumenschein W.M. McClanahan T. Hämmerling G. Li M.O. Cua D.J. McGeachy M.J. Foxp3(+) regulatory T cells promote T helper 17 cell development in vivo through regulation of interleukin-2.Immunity. 2011; 34: 409-421Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar, Pandiyan et al., 2011Pandiyan P. Conti H.R. Zheng L. Peterson A.C. Mathern D.R. Hernández-Santos N. Edgerton M. Gaffen S.L. Lenardo M.J. CD4(+)CD25(+)Foxp3(+) regulatory T cells promote Th17 cells in vitro and enhance host resistance in mouse Candida albicans Th17 cell infection model.Immunity. 2011; 34: 422-434Abstract Full Text Full Text PDF PubMed Google Scholar). One of the newest “lineages” of CD4+ T cells is the follicular helper T cell, which provides help to B cells in germinal centers. Cytokines like IL-6 and IL-21 signal via STAT3 and promote expression of Bcl6 and other molecules that contribute to the phenotype and function of this subset. However, IL-12 and STAT4 also turn out to be drivers of Tfh cells (Nakayamada et al., 2011Nakayamada S. Kanno Y. Takahashi H. Jankovic D. Lu K.T. Johnson T.A. Sun H.W. Vahedi G. Hakim O. Handon R. et al.Early Th1 cell differentiation is marked by a Tfh cell-like transition.Immunity. 2011; 35: 919-931Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar, Schmitt et al., 2009Schmitt N. Morita R. Bourdery L. Bentebibel S.E. Zurawski S.M. Banchereau J. Ueno H. Human dendritic cells induce the differentiation of interleukin-21-producing T follicular helper-like cells through interleukin-12.Immunity. 2009; 31: 158-169Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar). STAT4 directly binds many genes involved in Tfh cell differentiation, including Bcl6 and Il21. Conversely, IL-2 inhibits Tfh cell differentiation and once again, the action of STAT5 appears to be very direct. It competes with STAT3 binding to the Bcl6 locus and also promotes expression of Prdm1, which encodes Blimp1 (Johnston et al., 2012Johnston 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. 2012; 209: 243-250Crossref PubMed Scopus (45) Google Scholar, Oestreich et al., 2012Oestreich K.J. Mohn S.E. Weinmann A.S. Molecular mechanisms that control the expression and activity of Bcl-6 in T(H)1 cells to regulate flexibility with a T(FH)-like gene profile.Nat. Immunol. 2012; 13: 405-411Crossref PubMed Scopus (32) Google Scholar). Perhaps less surprising given its role in transmitting IL-4 signals, STAT6 is also an important regulator of the recently defined Th9 cells (Goswami et al., 2012Goswami R. Jabeen R. Yagi R. Pham D. Zhu J. Goenka S. Kaplan M.H. STAT6-dependent regulation of Th9 development.J. Immunol. 2012; 188: 968-975Crossref PubMed Scopus (33) Google Scholar). IL-7 and IL-15 are important for CD8+ T cell memory formation and accordingly STAT5A and STAT5B are also important (Hand et al., 2010Hand T.W. Cui W. Jung Y.W. Sefik E. Joshi N.S. Chandele A. Liu Y. Kaech S.M. Differential effects of STAT5 and PI3K/AKT signaling on effector and memory CD8 T-cell survival.Proc. Natl. Acad. Sci. USA. 2010; 107: 16601-16606Crossref PubMed Scopus (46) Google Scholar, Tripathi et al., 2010Tripathi P. Kurtulus S. Wojciechowski S. Sholl A. Hoebe K. Morris S.C. Finkelman F.D. Grimes H.L. Hildeman D.A. STAT5 is critical to maintain effector CD8+ T cell responses.J. Immunol. 2010; 185: 2116-2124Crossref PubMed Scopus (20) Google Scholar). STAT5A and STAT5B are essential for the survival of viral-specific CD8+ T cells and expression of Bcl-2. In contrast, in the setting of viral infection, the numbers of CD4+ effector T cells are unaffected by the absence of STAT5A and STAT5B. However, STAT5A and STAT5B are not the only family members important for CD8 cell function; STAT3 is also important, mediating signals by IL-10 and IL-21 (Cui et al., 2011Cui 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. 2011; 35: 792-805Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar). Expression of such key molecules as Eomes, Bcl-6, Blimp-1, and Socs-3 are all reduced in STAT3-deficient CD8 T cells. Defects in CD8+ T cell memory also occur in patients with hyperimmunoglobulin E syndrome and dominant-negative STAT3 mutations, which are associated with viral infection (Siegel et al., 2011Siegel A.M. Heimall J. Freeman A.F. Hsu A.P. Brittain E. Brenchley J.M. Douek D.C. Fahle G.H. Cohen J.I. Holland S.M. Milner J.D. A critical role for STAT3 transcription factor signaling in the development and maintenance of human T cell memory.Immunity. 2011; 35: 806-818Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar). IL-7, acting via STAT5A and STAT5B, is important in B lymphopoiesis, controlling survival and development (Malin et al., 2010Malin S. McManus S. Cobaleda C. Novatchkova M. Delogu A. Bouillet P. Strasser A. Busslinger M. Role of STAT5 in controlling cell survival and immunoglobulin gene recombination during pro-B cell development.Nat. Immunol. 2010; 11: 171-179Crossref PubMed Scopus (76) Google Scholar). Conversely, the B cell adaptor BLNK antagonizes IL-7 signaling via inhibition of JAK3, and absence of BLNK leads to constitutive JAK-STAT activation and leukomogenesis (Nakayama et al., 2009Nakayama J. Yamamoto M. Hayashi K. Satoh H. Bundo K. Kubo M. Goitsuka R. Farrar M.A. Kitamura D. BLNK suppresses pre-B-cell leukemogenesis through inhibition of JAK3.Blood. 2009; 113: 1483-1492Crossref PubMed Scopus (31) Google Scholar). In summary, as we learn more about T and B cells, critical roles for STATs continue to be revealed. Essential functions have been identified in recently recognized subsets of CD4+ T cells. In addition, other roles for STATs in classic subsets are also now recognized. STATs also have numerous functions in innate immunity—too many to review in detail here, but summarized in detail elsewhere (Murray, 2007Murray P.J. The JAK-STAT signaling pathway: input and output integration.J. Immunol. 2007; 178: 2623-2629PubMed Google Scholar, O'Shea and Murray, 2008O'Shea J.J. Murray P.J. Cytokine signaling modules in inflammatory responses.Immunity. 2008; 28: 477-487Abstract Full Text Full Text PDF PubMed Scopus (229) Google Scholar). The importance of STAT1 in mediating IFN effects has long been recognized, as has the role of STAT3 in IL-6 signaling and the acute phase response. Colony-stimulating factors and cytokines like granulocye macrophage-CSF, granulocyte-CSF, and IL-5, which regulate myeloid development, also signal via STATs. Consequently, STATs have key functions for neutrophils and macrophages (Nguyen-Jackson et al., 2010Nguyen-Jackson H. Panopoulos A.D. Zhang H. Li H.S. Watowich S.S. STAT3 controls the neutrophil migratory response to CXCR2 ligands by direct activation of G-CSF-induced CXCR2 expression and via modulation of CXCR2 signal transduction.Blood. 2010; 115: 3354-3363Crossref PubMed Scopus (24) Google Scholar, Panopoulos et al., 2006Panopoulos A.D. Zhang L. Snow J.W. Jones D.M. Smith A.M. El Kasmi K.C. Liu F. Goldsmith M.A. Link D.C. Murray P.J. Watowich S.S. STAT3 governs distinct pathways in emergency granulopoiesis and mature neutrophils.Blood. 2006; 108: 3682-3690Crossref PubMed Scopus (62) Google Scholar, Zhang et al., 2010aZhang H. Nguyen-Jackson H. Panopoulos A.D. Li H.S. Murray P.J. Watowich S.S. STAT3 controls myeloid progenitor growth during emergency granulopoiesis.Blood. 2010; 116: 2462-2471Crossref PubMed Scopus (31) Google Scholar). GM-CSF inhibits Flt3L-mediated plasmacytoid DC production and conventional DC growth and STAT5 is important in this process (Esashi et al., 2008Esashi E. Wang Y.H. Perng O. Qin X.F. Liu Y.J. Watowich S.S. The signal transducer STAT5 inhibits plasmacytoid dendritic cell development by suppressing transcription factor IRF8.Immunity. 2008; 28: 509-520Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar). In contrast, STAT3 is important for the expansion of DC progenitors. The importance of IL-22, acting via STAT3, in regulating the barrier function of epithelial cells and wound repair is a topic of considerable interest (Sonnenberg et al., 2011Sonnenberg G.F. Fouser L.A. Artis D. Border patrol: regulation of immunity, inflammation and tissue homeostasis at barrier surfaces by IL-22.Nat. Immunol. 2011; 12: 383-390Crossref PubMed Scopus (154) Google Scholar). Like IL-10, IL-22 is produced by and acts on innate immune cells and has critical anti-inflammatory properties. Precisely how STAT3 promotes inflammation in some circumstances and inhibits in others is an important but challenging question (El Kasmi et al., 2006El Kasmi K.C. Holst J. Coffre M. Mielke L. de Pauw A. Lhocine N. Smith A.M. Rutschman R. Kaushal D. Shen Y. et al.General nature of the STAT3-activated anti-inflammatory response.J. Immunol. 2006; 177: 7880-7888PubMed Google Scholar). STAT3 can negatively regulate IFN responses and has been proposed to inhibit TLR signaling either by inducing anti-inflammatory molecules or by a direct suppression of NF-κB (Wang et al., 2011Wang W.B. Levy D.E. Lee C.K. STAT3 negatively regulates type I IFN-mediated antiviral response.J. Immunol. 2011; 187: 2578-2585Crossref PubMed Scopus (9) Google Scholar). Nonetheless, a clear understanding of the pro- and anti-inflammatory actions of STAT3 remains elusive. Recently, the role of innate immune cells in promoting Th2 cell responses has become increasingly apparent. Thymic stromal lymphopoetin (TSLP) in particular is an important type I cytokine that promotes allergic responses. It acts on multiple cells, especially basophils, which are major producers of IL-4 (Siracusa et al., 2011Siracusa M.C. Saenz S.A. Hill D.A. Kim B.S. Headley M.B. Doering T.A. Wherry E.J. Jessup H.K. Siegel L.A. Kambayashi T. et al.TSLP promotes interleukin-3-independent basophil haematopoiesis and type 2 inflammation.Nature. 2011; 477: 229-233Crossref PubMed Scopus (94) Google Scholar, van Panhuys et al., 2011van Panhuys N. Prout M. Forbes E. Min B. Paul W.E. Le Gros G. Basophils are the major producers of IL-4 during primary helminth infection.J. Immunol. 2011; 186: 2719-2728Crossref PubMed Scopus (19) Google Scholar). The identity of the JAKs responsible for signaling had been enigmatic, but we now know that TSLP signals via JAK1 and JAK2 to activate STAT5 (Rochman et al., 2010Rochman Y. Kashyap M. Robinson G.W. Sakamoto K. Gomez-Rodriguez J. Wagner K.U. Leonard W.J. Thymic stromal lymphopoietin-mediated STAT5 phosphorylation via kinases JAK1 and JAK2 reveals a key difference from IL-7-induced signaling.Proc. Natl. Acad. Sci. USA. 2010; 107: 19455-19460Crossref PubMed Scopus (34) Google Scholar). In addition to the classical mode of activating macrophages via IFN-γ, the appreciation of the importance of Th2 cytokines in generating alternatively activated macrophages (AAMs) is now recognized. AAMs appear to be important in a range of processes including host defense, fibrosis, metabolic regulation, obesity, and cancer. As IL-4 and IL-13 are major drivers of the AAM, STAT6 is a key player for these cells. STAT6 is important in regulating insulin action, lipid metabolism, and expression of proliferation-activated receptor isoforms (Ricardo-Gonzalez et al., 2010Ricardo-Gonzalez R.R. Red Eagle A. Odegaard J.I. Jouihan H. Morel C.R. Heredia J.E. Mukundan L. Wu D. Locksley R.M. Chawla A. IL-4/STAT6 immune axis regulates peripheral nutrient metabolism and insulin sensitivity.Proc. Natl. Acad. Sci. USA. 2010; 107: 22617-22622Crossref PubMed Scopus (33) Google Scholar, Szanto et al., 2010Szanto A. Balint B.L. Nagy Z.S. Barta E. Dezso B. Pap A. Szeles L. Poliska S. Oros M. Evans R.M. et al.STAT6 transcription factor is a facilitator of the nuclear receptor PPARγ-regulated gene expression in macrophages and dendritic cells.Immunity. 2010; 33: 699-712Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar). Very recently, AAMs and STAT6 have been implicated in the mammalian thermogenic response (Nguyen et al., 2011Nguyen K.D. Qiu Y. Cui X. Goh Y.P. Mwangi J. David T. Mukundan L. Brombacher F. Locksley R.M. Chawla A. Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis.Nature. 2011; 480: 104-108Crossref PubMed Scopus (91) Google Scholar). Intriguingly, AAMs secrete catacholamines in a STAT6-dependent manner and induce thermogenic gene expression in brown adipose tissue and lipolysis in white adipose tissue. Beyond their role as transcription factors, a direct role of STATs in mitochondrial function makes the argument for key roles in metabolism even more compelling (Gough et al., 2009Gough D.J. Corlett A. Schlessinger K. Wegrzyn J. Larner A.C. Levy D.E. Mitochondrial STAT3 supports Ras-dependent oncogenic transformation.Science. 2009; 324: 1713-1716Crossref PubMed Scopus (167) Google Scholar, Potla et al., 2006Potla R. Koeck T. Wegrzyn J. Cherukuri S. Shimoda K. Baker D.P. Wolfman J. Planchon S.M. Esposito C. Hoit B. et al.Tyk2 tyrosine kinase expression is required for the maintenance of mitochondrial respiration in primary pro-B lymphocytes.Mol. Cell. Biol. 2006; 26: 8562-8571Crossref PubMed Scopus (19) Google Scholar, Wegrzyn et al., 2009Wegrzyn J. Potla R. Chwae Y.J. Sepuri N.B. Zhang Q. Koeck T. Derecka M. Szczepanek K. Szelag M. Gornicka A. et al.Function of mitochondrial Stat3 in cellular respiration.Science. 2009; 323: 793-797Crossref PubMed Scopus (199) Google Scholar). Although it has long been recognized that viruses can disrupt IFN signaling by disrupting STAT signaling (Ramachandran and Horvath, 2009Ramachandran A. Horvath C.M. Paramyxovirus disruption of interferon signal transduction: STATus report.J. Interferon Cytokine Res. 2009; 29: 531-537Crossref PubMed Scopus (29) Google Scholar), recent work shows that T. gondii alters host response by injecting the kinase ROP16 and activating both STAT3 and STAT6 (Butcher et al., 2011Butcher B.A. Fox B.A. Rommereim L.M. Kim S.G. Maurer K.J. Yarovinsky F. Herbert D.R. Bzik D.J. Denkers E.Y. Toxoplasma gondii rhoptry kinase ROP16 activates STAT3 and STAT6 resulting in cytokine inhibition and arginase-1-dependent growth control.PLoS Pathog. 2011; 7: e1002236Crossref PubMed Scopus (30) Google Scholar, Saeij et al., 2007Saeij J.P. Coller S. Boyle J.P. Jerome M.E. White M.W. Boothroyd J.C. Toxoplasma co-opts host gene expression by injection of a polymorphic kinase homologue.Nature. 2007; 445: 324-327Crossref PubMed Scopus (211) Google Scholar). In macrophages, the effect is downregulation of proinflammatory cytokine signaling and deviation to an alternatively activated phenotype. Viruses can also activate STAT6 and can do so apparently in a JAK-independent manner (Chen et al., 2011aChen H. Sun H. You F. Sun W. Zhou X. Chen L. Yang J. Wang Y. Tang H. Guan Y. et al.Activation of STAT6 by STING is critical for antiviral innate immunity.Cell. 2011; 147: 436-446Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar). In this case though, Stat6 activation is protective in terms of host response. The advent of chromatin precipitation and massive parallel sequencing (ChIP-Seq) has permitted the understanding of STAT action on a global scale. Analysis of the genome-wide targets of STATs via ChIP-Seq analysis for all the STATs has now been obtained, albeit in a limited number of tissues with relatively few stimuli and time points. Gene expression is dramatically influenced by chromatin organization and until recently, the importance of STATs in regulating epigenetics has been implicated only by analysis of selected regions of certain genes. However, recent technologies in measuring cell-specific transcriptomes and epigenomes, coupled with the use of gene-targeted mice, allows assessments of the global impact of STAT-dependent signaling. What emerges is that STATs have thousands of genomic targets and have major effects on transcription and epigenetic modifications (Durant et al., 2010Durant L. Watford W.T. Ramos H.L. Laurence A. Vahedi G. Wei L. Takahashi H. Sun H.W. Kanno Y. Powrie F. O'Shea J.J. Diverse targets of the transcription factor STAT3 contribute to T cell pathogenicity and homeostasis.Immunity. 2010; 32: 605-615Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar, Elo et al., 2010Elo L.L. Järvenpää H. Tuomela S. Raghav S. Ahlfors H. Laurila K. Gupta B. Lund R.J. Tahvanainen J. Hawkins R.D. et al.Genome-wide profiling of interleukin-4 and STAT6 transcription factor regulation of human Th2 cell programming.Immunity. 2010; 32: 852-862Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, Good et al., 2009Good S.R. Thieu V.T. Mathur A.N. Yu Q. Stritesky G.L. Yeh N. O'Malley J.T. Perumal N.B. Kaplan M.H. Temporal induction pattern of STAT4 target genes defines potential for Th1 lineage-specific programming.J. Immunol. 2009; 183: 3839-3847Crossref PubMed Scopus (15) Google Scholar, Liao et al., 2011aLiao W. Lin J.X. Leonard W.J. IL-2 family cytokines: new insights into the complex roles of IL-2 as a broad regulator of T helper cell differentiation.Curr. Opin. Immunol. 2011; 23: 598-604Crossref

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