T-cell Development and Function Are Modulated by Dual Specificity Phosphatase DUSP5

Abstract

Interleukin-2 (IL-2) is a pleiotropic cytokine that regulates lymphocyte proliferation and peripheral tolerance. IL-2 activates mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase, and signal transducer and activator of transcription (STAT) pathways and modulates expression of target genes. Systematic analysis of IL-2 target genes has revealed regulation of potential feedback inhibitors of IL-2 signaling, including several suppressor of cytokine signaling (SOCS) family members as well as MAPK pathway-regulating dual specificity phosphatases (DUSPs). Here we have evaluated the in vivo actions of DUSP5, an extracellular signal-regulated kinase 1/2 (ERK1/2)-specific phosphatase, by generating transgenic mice overexpressing DUSP5 within the lymphoid compartment. We show that transgenic DUSP5 expression results in a block in thymocyte development at the double positive stage. We also demonstrate that DUSP5-expressing mature T cells exhibit decreased IL-2-dependent proliferation and defective IL-2-mediated induction of genes. Finally, DUSP5 transgenic mice develop autoimmune symptoms, suggesting a role for the MAPK pathway in the regulation of tolerance. Thus, proper regulation of DUSP5 activity is critical for normal immune system development, IL-2 actions, and tolerance. Interleukin-2 (IL-2) is a pleiotropic cytokine that regulates lymphocyte proliferation and peripheral tolerance. IL-2 activates mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase, and signal transducer and activator of transcription (STAT) pathways and modulates expression of target genes. Systematic analysis of IL-2 target genes has revealed regulation of potential feedback inhibitors of IL-2 signaling, including several suppressor of cytokine signaling (SOCS) family members as well as MAPK pathway-regulating dual specificity phosphatases (DUSPs). Here we have evaluated the in vivo actions of DUSP5, an extracellular signal-regulated kinase 1/2 (ERK1/2)-specific phosphatase, by generating transgenic mice overexpressing DUSP5 within the lymphoid compartment. We show that transgenic DUSP5 expression results in a block in thymocyte development at the double positive stage. We also demonstrate that DUSP5-expressing mature T cells exhibit decreased IL-2-dependent proliferation and defective IL-2-mediated induction of genes. Finally, DUSP5 transgenic mice develop autoimmune symptoms, suggesting a role for the MAPK pathway in the regulation of tolerance. Thus, proper regulation of DUSP5 activity is critical for normal immune system development, IL-2 actions, and tolerance. Interleukin-2 (IL-2) 4The abbreviations used are: IL, interleukin; MAPK, mitogen-activated protein kinase; STAT, signal transducer and activator of transcription; ERK, extracellular signal-regulated kinase; WT, wild type; FBS, fetal bovine serum; PBS, phosphate-buffered saline; JNK, c-Jun N-terminal kinase; DUSP, dual specificity phosphatase. is a cytokine with pleiotropic actions (1Lin J.X. Leonard W.J. Thomson A. Lotze M.T. The Cytokine Handbook. Academic Press, New York2003: 167-199Google Scholar). IL-2 was originally characterized as a T-cell growth factor (2Morgan D.A. Ruscetti F.W. Gallo R. Science. 1975; 193: 1007-1008Crossref Scopus (1862) Google Scholar), but subsequently was shown to mediate activation-induced cell death (3Lenardo M.J. Nature. 1991; 353: 858-861Crossref PubMed Scopus (983) Google Scholar), to support the development and maintenance of CD4+CD25+ regulatory T cells involved in the regulation of peripheral tolerance (4Malek T.R. J. Leukoc. Biol. 2003; 74: 961-965Crossref PubMed Scopus (267) Google Scholar), to expand CD8+ T cells during secondary immune responses (5Williams M.A. Tyznik A.J. Bevan M.J. Nature. 2006; 441: 890-893Crossref PubMed Scopus (616) Google Scholar), and to have a range of actions beyond T cells as well (6Lin J.X. Leonard W.J. Cytokine Growth Factor Rev. 1997; 8: 313-332Crossref PubMed Scopus (144) Google Scholar). IL-2 mediates its biologic actions by triggering a signaling cascade after binding to intermediate or high-affinity IL-2 receptors (IL-2R) (7Leonard W.J. O'Shea J.J. Annu. Rev. Immunol. 1998; 16: 293-322Crossref PubMed Scopus (1528) Google Scholar, 8Kovanen P.E. Leonard W.J. Immunol. Rev. 2004; 202: 67-83Crossref PubMed Scopus (327) Google Scholar, 9Kim H.P. Imbert J. Leonard W.J. Cytokine Growth Factor Rev. 2006; 17: 349-366Crossref PubMed Scopus (247) Google Scholar). This causes the phosphorylation and activation of receptor-associated tyrosine kinases, Jak1 and Jak3. These in turn mediate the phosphorylation of tyrosine residues in the IL-2Rβ cytoplasmic domain that serve as docking sites for Shc, which couples to the Ras/mitogen-activated protein kinase (MAPK) pathway, and signal transducer and activator of transcription (STAT) proteins. IL-2 also activates phosphatidylinositol 3-kinase. Collectively, these pathways contribute to T-cell survival and proliferation and the generation of regulatory T cells (8Kovanen P.E. Leonard W.J. Immunol. Rev. 2004; 202: 67-83Crossref PubMed Scopus (327) Google Scholar). The different signaling pathways regulate the actions of IL-2 in part by regulating expression of IL-2 target genes, such as IL-2Rα, cyclin D2, Pim-1, Bcl-2, and granzyme B (8Kovanen P.E. Leonard W.J. Immunol. Rev. 2004; 202: 67-83Crossref PubMed Scopus (327) Google Scholar). Interestingly, IL-2 induces the expression of several feedback inhibitors of signaling, including suppressors of cytokine signaling family members SOCS1 and CIS, which provide general inhibitory signals or more specifically inhibit Stat5 proteins, respectively (10Aman M.J. Migone T.S. Sasaki A. Ascherman D.P. Zhu M. Soldaini E. Imada K. Miyajima A. Yoshimura A. Leonard W.J. J. Biol. Chem. 1999; 274: 30266-30272Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar, 11Sporri B. Kovanen P.E. Sasaki A. Yoshimura A. Leonard W.J. Blood. 2001; 97: 221-226Crossref PubMed Scopus (111) Google Scholar, 12Cornish A.L. Chong M.M. Davey G.M. Darwiche R. Nicola N.A. Hilton D.J. Kay T.W. Starr R. Alexander W.S. J. Biol. Chem. 2003; 278: 22755-22761Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar), as well as the dual specificity phosphatases DUSP5 and DUSP6 (13Kovanen P.E. Rosenwald A. Fu J. Hurt E.M. Lam L.T. Giltnane J.M. Wright G. Staudt L.M. Leonard W.J. J. Biol. Chem. 2003; 278: 5205-5213Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar, 14Kovanen P.E. Young L. Al-Shami A. Rovella V. Pise-Masison C.A. Radonovich M.F. Powell J. Fu J. Brady J.N. Munson P.J. Leonard W.J. Int. Immunol. 2005; 17: 1009-1021Crossref PubMed Scopus (47) Google Scholar), which can inhibit the activity of extracellular signal-regulated kinases 1/2 (ERK1/2), suggesting careful control by IL-2 of MAPK activity. MAPKs are evolutionarily conserved serine-threonine kinases that convert extracellular stimuli to intracellular signaling events, regulating cellular processes such as proliferation, differentiation, and apoptosis (15Chang L. Karin M. Nature. 2001; 410: 37-40Crossref PubMed Scopus (4472) Google Scholar, 16Johnson G.L. Lapadat R. Science. 2002; 298: 1911-1912Crossref PubMed Scopus (3618) Google Scholar). Four major groups of MAPKs have been identified, including ERKs (ERK1, ERK2, and ERK5), c-Jun N-terminal kinases (JNK; JNK1, JNK2, and JNK3), p38 MAPKs (p38α, p38β, p38γ and p38δ), and ERK5/Big MAP kinase 1 (BMK1). MAPKs are activated by a phosphorylation cascade that involves activation of MAPK kinases (MAPKK; MEK1, MEK2, MKK3–7) by extracellular activators including growth factors, cytokines, or oxidative stress via distinct signaling molecules such as Ras and Raf. Distinct MAPKKs activate different MAPKs. For example, MEK1 and MEK2 activate ERK1 and ERK2, MKK3 and MKK4 activate p38 MAPK, MKK4 and MKK7 activate JNK, and MKK5 activates ERK5. The substrates of MAPKs include transcription factors such as Elk-1, ATF2, and c-Jun, as well as other signaling molecules such as ribosomal S6 kinases (Rsks) (15Chang L. Karin M. Nature. 2001; 410: 37-40Crossref PubMed Scopus (4472) Google Scholar). MAPKs are essential for normal immune function, contributing to T-cell development and function (17Rincon M. Flavell R.A. Davis R.J. Oncogene. 2001; 20: 2490-2497Crossref PubMed Scopus (108) Google Scholar, 18Dong C. Davis R.J. Flavell R.A. Annu. Rev. Immunol. 2002; 20: 55-72Crossref PubMed Scopus (1417) Google Scholar). For example, p38 MAPK negatively regulates early T-lymphocyte development in the thymus (19Starr T.K. Jameson S.C. Hogquist K.A. Annu. Rev. Immunol. 2003; 21: 139-176Crossref PubMed Scopus (1225) Google Scholar), ERK1/2 have an important role in T-cell positive selection (20Sharp L.L. Schwarz D.A. Bott C.M. Marshall C.J. Hedrick S.M. Immunity. 1997; 7: 609-618Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar, 21Pages G. Guerin S. Grall D. Bonino F. Smith A. Anjuere F. Auberger P. Pouyssegur J. Science. 1999; 286: 1374-1377Crossref PubMed Scopus (548) Google Scholar), and JNK is needed for T-lymphocyte negative selection (22Rincon M. Whitmarsh A. Yang D.D. Weiss L. Derijard B. Jayaraj P. Davis R.J. Flavell R.A. J. Exp. Med. 1998; 188: 1817-1830Crossref PubMed Scopus (193) Google Scholar). JNK-deficient T cells are defective in IFN-γ production and Th1 cell function (23Dong C. Yang D.D. Wysk M. Whitmarsh A.J. Davis R.J. Flavell R.A. Science. 1998; 282: 2092-2095Crossref PubMed Scopus (536) Google Scholar). p38 MAPK also appears to regulate Th1 cytokine production (24Rincon M. Enslen H. Raingeaud J. Recht M. Zapton T. Su M.S. Penix L.A. Davis R.J. Flavell R.A. EMBO J. 1998; 17: 2817-2829Crossref PubMed Scopus (362) Google Scholar, 25Lu H.T. Yang D.D. Wysk M. Gatti E. Mellman I. Davis R.J. Flavell R.A. EMBO J. 1999; 18: 1845-1857Crossref PubMed Scopus (328) Google Scholar). As noted above, MAPKs can be regulated by DUSPs. Ten distinct DUSPs with MAPK phosphatase activity (DUSP1, 2, 4, 5, 6, 7, 8, 9, 10, and 16) contain an N-terminal MAPK targeting domain and a C-terminal catalytic domain that can dephosphorylate both serine-threonine and tyrosine residues (26Keyse S.M. Curr. Opin. Cell Biol. 2000; 12: 186-192Crossref PubMed Scopus (716) Google Scholar, 27Theodosiou A. Ashworth A. Genome Biol. 2002; 3 (REVIEWS3009)Crossref PubMed Google Scholar, 28Liu Y. Shepherd E.G. Nelin L.D. Nat. Rev. Immunol. 2007; 7: 202-212Crossref PubMed Scopus (525) Google Scholar). Different DUSPs are specific for distinct MAPKs. For example, DUSP5 and DUSP6 are specific for ERK1 and ERK2, whereas DUSP8, DUSP10, and DUSP16 regulate JNK and p38 MAPK. We identified DUSP5 as an IL-2-regulated gene that can act as a negative feedback regulator of the MAPK pathway in the context of IL-2 signaling (13Kovanen P.E. Rosenwald A. Fu J. Hurt E.M. Lam L.T. Giltnane J.M. Wright G. Staudt L.M. Leonard W.J. J. Biol. Chem. 2003; 278: 5205-5213Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar). DUSP5 is a nuclear phosphatase that acts on ERK1/2 but not on JNK or p38 MAPK (29Ishibashi T. Bottaro D.P. Michieli P. Kelley C.A. Aaronson S.A. J. Biol. Chem. 1994; 269: 29897-29902Abstract Full Text PDF PubMed Google Scholar, 30Mandl M. Slack D.N. Keyse S.M. Mol. Cell. Biol. 2005; 25: 1830-1845Crossref PubMed Scopus (161) Google Scholar). In T cells, DUSP5 is also induced by IL-7 and IL-15 but not by IL-4 (13Kovanen P.E. Rosenwald A. Fu J. Hurt E.M. Lam L.T. Giltnane J.M. Wright G. Staudt L.M. Leonard W.J. J. Biol. Chem. 2003; 278: 5205-5213Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar). To clarify the actions of DUSP5, we generated transgenic (Tg) mice that overexpress DUSP5 in T cells. These mice exhibit defective thymic T-cell development, with a block at the double positive (DP) stage and decreased numbers of mature CD4+ and CD8+ T cells, indicating a role for MAPK in the establishment of these cell populations. Generation of DUSP5 Tg Mice—A human DUSP5 cDNA with a C-terminal c-Myc epitope tag (kindly provided by Dr. Jack E. Dixon) was cloned between the XbaI and ClaI sites of the pHSE vector containing the H2-Kb promoter, β-globin exons 2 and 3 plus polyadenylation signal, and immunoglobulin heavy chain enhancer (Fig. 1A). The transgenic DNA was the of mice The to the stage of development and of to in Academic Press, Scholar). to these for the of by specific and to the expression was by to DUSP5 that we generated We not between the and DUSP5 Tg Tg by the and and of C-terminal of human DUSP5 which has with DUSP5, was used to the and after We evaluated and specific by a protein and specific of and used to DUSP5 expression in T cells T cell and B cells in 1 1 plus for or in 1 1 plus phosphatase 1 and 2 protein with with and for The on or and to or with in for and or bovine in for Cell and Cell and and Cell The with and with secondary and was used for or with secondary and and signals an system cell thymus and and a and a with or The used and and and and and shown are of at DUSP5 Tg Cell and ERK1/2 activation cell of and DUSP5 Tg mice or not with with and at for and protein for For activation of T cell of T cells T cell or CD8+ cells and DUSP5 Tg mice for 3 with and and in containing FBS, 2 and with for a of at on 3 and in with for at 1 in For and ERK1/2 cell of T cells and DUSP5 Tg mice or not with IL-2 and at for 5, 10, and and protein for and the role of DUSP5 in thymic selection events, we the in vivo of induced by and DUSP5 Tg with or of in of PBS, and for and analysis 2 after cell of T and activated T cells or DUSP5 Tg mice for and T or T in in at 2 or 1 and activated T or IL-2 was with 1 of for the of and CD8+ T cells and DUSP5 Tg mice and activated for as for with IL-2 for was and to for analysis The to Genome and and of or generated For a was to the signals by to the The was to the for cells and DUSP5 Tg mice to for expression after IL-2 These the as at of for a a or of a of and a of used to the of genes Y. Y. J. B. Scholar, Y. D. G. I. 2001; PubMed Scopus Google Scholar). and and in in and at with and with DNA in PBS, at with in PBS, and 1 at in DNA was and for 1 at with or DUSP5 Tg in with 1 at with or in in PBS, the was development, the was with and at of used to of We that IL-2 regulates DUSP5 and protein in T (13Kovanen P.E. Rosenwald A. Fu J. Hurt E.M. Lam L.T. Giltnane J.M. Wright G. Staudt L.M. Leonard W.J. J. Biol. Chem. 2003; 278: 5205-5213Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar, 14Kovanen P.E. Young L. Al-Shami A. Rovella V. Pise-Masison C.A. Radonovich M.F. Powell J. Fu J. Brady J.N. Munson P.J. Leonard W.J. Int. Immunol. 2005; 17: 1009-1021Crossref PubMed Scopus (47) Google Scholar). To more the actions of DUSP5, we generated Tg mice in which DUSP5 was the control of the H2-Kb and immunoglobulin heavy chain enhancer (Fig. which expression in and cells H. T.W. R. E. H. K. EMBO J. 8: PubMed Scopus Google Scholar, D. J. Exp. Med. PubMed Scopus Google Scholar). We with DUSP5 expression in both thymus and are which not thymic or cell numbers (Fig. in thymic or development (Fig. we a of the DUSP5 on lymphocyte development by The DUSP5 Tg mice in CD4+ and CD8+ positive with a in the of (Fig. The numbers of early double negative to to in not but with the of DUSP5 Tg mice of CD4+ and CD8+ T cells (Fig. a of CD8+ T cells DUSP5 Tg mice a was in (Fig. of the CD4+ T cells DUSP5 Tg also an activated not The numbers of T cells (Fig. and cells (Fig. in DUSP5 Tg The of cells was more in the DUSP5 Tg mice (Fig. a role for ERK1/2 in cell differentiation, as was L. J. J. Immunol. 2006; PubMed Scopus Google Scholar). We not in the of CD4+CD25+ regulatory T cells not thymocyte development in DUSP5 Tg mice was at the we the of DUSP5 transgenic expression on ERK1/2 phosphorylation in (Fig. and DUSP5 Tg mice activated with and the phosphorylation of ERK1/2 was by induced an in ERK1/2 phosphorylation in cells, was in cells DUSP5 Tg indicating that transgenic DUSP5 ERK1/2 ERKs to positive but not negative selection (20Sharp L.L. Schwarz D.A. Bott C.M. Marshall C.J. Hedrick S.M. Immunity. 1997; 7: 609-618Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar, 21Pages G. Guerin S. Grall D. Bonino F. Smith A. Anjuere F. Auberger P. Pouyssegur J. Science. 1999; 286: 1374-1377Crossref PubMed Scopus (548) Google Scholar), we the of to mediate the of (22Rincon M. Whitmarsh A. Yang D.D. Weiss L. Derijard B. Jayaraj P. Davis R.J. Flavell R.A. J. Exp. Med. 1998; 188: 1817-1830Crossref PubMed Scopus (193) Google Scholar). and DUSP5 Tg mice in thymocyte cell numbers after (Fig. with the of a role for DUSP5 and ERKs in activation is with proliferation, we that the decreased of mature CD4+ and CD8+ T cells in DUSP5 Tg mice (Fig. have T-cell proliferation, a that involves both and is that that the cytokine chain are important for B. M. Nat. Rev. Immunol. 2004; PubMed Scopus Google Scholar, Immunol. Rev. 2005; PubMed Scopus Google Scholar, I. C. Immunol. Rev. 2006; PubMed Scopus Google Scholar). As mice proliferation in to G. Guerin S. Grall D. Bonino F. Smith A. Anjuere F. Auberger P. Pouyssegur J. Science. 1999; 286: 1374-1377Crossref PubMed Scopus (548) Google Scholar), we the of and IL-2 on or DUSP5 Tg DUSP5 Tg mice proliferation in to with or as with cells mice (Fig. numbers of or numbers of DUSP5 Tg mice (Fig. have been for the proliferation, we the of and IL-2 on mature T or DUSP5 Tg T cells or DUSP5 Tg mice proliferation in to plus or IL-2 (Fig. after activation and IL-2 T cells DUSP5 Tg mice proliferation in to IL-2 (Fig. IL-2 is to activate several signaling pathways in to including the and phosphatidylinositol To the signaling pathways that be defective in DUSP5 Tg T cells, we by the phosphorylation of and ERK1/2 in T cells with the phosphorylation of Stat5 and was in T cells or DUSP5 Tg ERK1/2 phosphorylation was in DUSP5 Tg in T cells (Fig. To the signaling pathways that be defective in DUSP5 Tg T cells, we CD8+ T cells and DUSP5 Tg and gene expression Genome are in We identified genes expression was regulated by IL-2 in mice of which are Stat5 target genes (13Kovanen P.E. Rosenwald A. Fu J. Hurt E.M. Lam L.T. Giltnane J.M. Wright G. Staudt L.M. Leonard W.J. J. Biol. Chem. 2003; 278: 5205-5213Abstract Full Text Full Text PDF PubMed Scopus (83) Google and in T cells both and DUSP5 Tg mice on genes is shown in Interestingly, of the not after IL-2 in T cells DUSP5 Tg mice We that at of these IL-2 target genes are or regulated by ERK1/2 on genes not induced by IL-2 in T cells DUSP5 Tg mice are shown in be to which of these genes contribute to the in the DUSP5 Tg we have transgenic DUSP5 expression as positive T-cell development and regulating a range of target genes. was that T cells DUSP5 Tg mice also to exhibit an activated and that was an in the of cells, on with (Fig. of mice in the revealed the development of in a of that was with (Fig. a of mice mice and DUSP5 Tg Tg at an of 3 to DUSP5 Tg mice not show at the of to of the at the of to the DUSP5 Tg mice with of specific not (Fig. mice DUSP5 Tg with an of DUSP5 Tg mice mice (Fig. 5, revealed with and cell and (Fig. 5, The transgenic mice with also in (Fig. 5, and not to or death within 2 of development of the These that DUSP5 transgenic expression to an We that IL-2 regulates the of several potential feedback of signaling including DUSP5 (13Kovanen P.E. Rosenwald A. Fu J. Hurt E.M. Lam L.T. Giltnane J.M. Wright G. Staudt L.M. Leonard W.J. J. Biol. Chem. 2003; 278: 5205-5213Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar, 14Kovanen P.E. Young L. Al-Shami A. Rovella V. Pise-Masison C.A. Radonovich M.F. Powell J. Fu J. Brady J.N. Munson P.J. Leonard W.J. Int. Immunol. 2005; 17: 1009-1021Crossref PubMed Scopus (47) Google Scholar). Here we have the role of DUSP5 in T-cell development and function by generating DUSP5 Tg These mice show decreased numbers of both thymic and CD4+ and CD8+ with the of ERK1/2 by DUSP5, ERK1/2 has been shown to be important for positive The negative feedback signals involved in the regulation of MAPK activity in the thymus have not been MAPK phosphatases are for MAPK phosphatases to the family of dual specificity which exhibit both of specific expression as well as distinct different MAPKs Y. Shepherd E.G. Nelin L.D. Nat. Rev. Immunol. 2007; 7: 202-212Crossref PubMed Scopus (525) Google Scholar, T. T. Nat. Rev. Immunol. 2005; PubMed Scopus Google Scholar). The thymic expression of different DUSPs was and 2, 5, 6, 10, and to be at a Mol. Immunol. 2006; PubMed Scopus Google Scholar). DUSP5 and DUSP6 in to with with regulation of DUSP5 is specific for a potential in vivo regulator of positive we that DUSP5 thymocyte development at the suggesting that the ERK1/2 pathway is not essential to to or that activation of ERK1/2 is for In thymocyte well in the of transgenic DUSP5, suggesting that ERK1/2 not regulate negative is by both and signals B. M. Nat. Rev. Immunol. 2004; PubMed Scopus Google Scholar, Nat. Rev. Immunol. 2002; PubMed Scopus Google Scholar). IL-7 and regulate the growth of CD4+ T cells E. E. R. J. S. A. 2001; PubMed Scopus Google Scholar, Immunol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, A. R. J. T. A. Leonard W.J. J. Exp. Med. 2004; PubMed Scopus Google Scholar), whereas IL-7 and and to IL-2 have been to regulate the of and CD8+ T cells D. K. R. A. R. J. Exp. Med. 2002; PubMed Scopus Google Scholar, B. E. J. J. Exp. Med. 2002; PubMed Scopus Google Scholar, M. J. Science. 2006; PubMed Scopus Google Scholar). DUSP5 Tg mice decreased numbers of CD4+ and CD8+ T cells, which at in decreased thymic we that DUSP5 also with In support of activated T cells DUSP5 Tg mice decreased proliferation in to with a activation of ERK1/2 IL-2 To the growth was with defective induction of genes, we the IL-2 regulation of gene expression in the CD8+ T cells DUSP5 Tg We that DUSP5 transgenic expression the expression of genes regulated by IL-2 in activated T cells as these genes not include of Stat5 (Fig. which is a well characterized of IL-2-dependent genes expression was have been shown to regulate cell proliferation, including and (Fig. which are of MAPK in other cellular E. C. R. A. V. L. S. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, Starr T.K. Hogquist K.A. S. A. 2005; PubMed Scopus Google Scholar). T cells DUSP5 Tg mice an activated with expression of IL-2Rβ and on both CD4+ and CD8+ T cells. As the mice to develop autoimmune of revealed in both and suggesting an autoimmune We also of in the of DUSP5 Tg have been in mice defective in function J.J. N.A. Immunity. 2002; 17: Full Text Full Text PDF PubMed Scopus Google Scholar, K. G. A. A. S. T. N.A. D. J. L. B. 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