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Rho GTPase-mediated pathways in mature CD4+ T cells
Autoimmunity Reviews 8 (2009) 199–203
Contents lists available at ScienceDirect
Autoimmunity Reviews j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / a u t r ev
Rho GTPase-mediated pathways in mature CD4+ T cells☆ Alessandra B. Pernis ⁎ Department of Medicine, Columbia University, 630 West 168th Street, New York, NY 10032, United States
a r t i c l e
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Available online 22 August 2008 Keywords: Systemic Lupus Erythematosus (SLE) Guanine nucleotide exchange factor (GEF) Rho GTPase activating protein (GAP) Rho GDP-dissociation inhibitor (RhoGDI) IRF-4 Binding Protein (IBP)
a b s t r a c t Effective immune responses require the appropriate activation and differentiation of peripheral CD4+ Tcells. These processes need to be followed by the timely elimination of the responding Tcells in order to restore T cell homeostasis. Defects in the appropriate regulation of T cell activation, expansion, and survival underlie the pathogenesis of many autoimmune disorders including SLE. The molecular machinery employed by T cells to properly control these processes and prevent the onset of autoimmunity has not been fully elucidated. Rho GTPases (which include the Rac, Cdc42, and Rho subfamilies) are molecular switches that control a wide range of cellular processes. Their fundamental role in biology is due to their ability to regulate both cytoskeletal dynamics and a large number of signal transduction pathways. Activation of Rho GTPases is now recognized as a key event in the coordination of immune responses and, particularly, in the activation of T cells. In this review, we will first provide an overview of the role of Rho GTPase-mediated pathways in mature CD4+ T cells and then we will discuss recent studies, which suggest that deregulation of these pathways may play a role in the pathogenesis of SLE. © 2008 Published by Elsevier B.V.
Contents 1. Introduction . . . . . . . . . . . . . . . . . . 2. Rho GTPase-mediated pathways: the basic scheme 3. Role of Rho GTPases in mature T cells . . . . . . 4. Role of Rho GTPase activators in mature T cells . . 5. Conclusions . . . . . . . . . . . . . . . . . . . Take-home messages . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction Defects in the appropriate regulation of T cell activation, expansion, and survival play a crucial role in the pathogenesis of Systemic Lupus Erythematosus (SLE) [1]. The molecular machinery employed by the immune system to prevent the development of autoimmune disorders like SLE is not fully understood. Rho GTPases are molecular switches that control a wide range of
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biological processes due to their capacity to regulate both signaling pathways as well as cytoskeletal reorganization [2]. In this review, which is part of a series on signaling pathways in SLE, we will provide an overview of the role of Rho GTPase-mediated pathways in mature T lymphocytes, and discuss recent studies, which suggest that deregulation of these pathways may participate in the pathogenesis of SLE. 2. Rho GTPase-mediated pathways: the basic scheme
☆ Research support is provided by NIH grant R01 HL-62215, the Lupus Research Institute, and the Alliance for Lupus Research. ⁎ Tel.: +212 305 3763; fax: +212 305 4478. E-mail address: [email protected]. 1568-9972/$ – see front matter © 2008 Published by Elsevier B.V. doi:10.1016/j.autrev.2008.07.044
The Rho family of GTPases is a large family of proteins, which includes RhoA, Rac1, Rac2, and Cdc42 [2]. Like other small GTPases, Rho GTPases behave like “molecular switches”
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that cycle between an inactive, GDP-bound, and an active, GTPbound, state (Fig. 1). The major class of proteins responsible for the activation of Rho GTPases is the Dbl family of guanine nucleotide exchange factors (GEFs) [3]. These GEFs catalyze the release of GDP leading to the formation of active GTP-bound Rho GTPases. Members of the Dbl family are characterized by the presence of a catalytic Dbl-homology (DH) domain followed by a C-terminal PH domain necessary for proper intracellular localization and function. Recent studies have revealed the existence of additional classes of activators for Rho GTPases. In particular, SWAP-70 was found to be a novel type of activator for Rac, in which a DH-like domain is flanked at its N-terminus, rather than at its C-terminus, by a PH domain [4]. A new family of GEFs characterized by the presence of a different domain termed the Dock homology region (DHR)-2 domain has also been identified [5]. The ability of GEFs to activate Rho GTPases is itself strictly regulated since GEFs normally exist in an inactive state and become activated in response to extracellular stimuli via either phosphorylation, changes in subcellular localization, or interaction with cofactors. A number of inhibitory systems are also in place to ensure that activation of Rho GTPases is tightly regulated. Proteins called GAPs (Rho GTPase activating proteins) inhibit the activation of Rho GTPases by increasing the weak intrinsic GTPase activity of Rho GTPases thus promoting their conversion to an inactive GDP-bound state [6]. A different family of molecules called RhoGDIs (Rho GDP-dissociation inhibitors) instead interferes with the activation of Rho GTPases by preventing the dissociation of GDP and by blocking their recruitment to the plasma membrane, a step that is necessary for the interaction of Rho GTPases with GEFs [7]. Once they become activated Rho GTPases control cytoskeletal dynamics as well as numerous signaling pathways due to their capacity to bind to and activate a large number of downstream effector molecules, which include serine/threonine kinases, lipid kinases, and adaptors [2]. Rac and Cdc42 can bind to many of the same effectors like the PAK kinases. RhoA instead usually targets a different set of effectors, like the Rhoassociated coiled-coil-containing protein kinases (ROCK-I and
ROCK-II) and thus often regulates distinct signaling and cytoskeletal events. Due to their ability to target multiple pathways, Rho GTPases have been implicated in the control of a wide range of biological processes such as proliferation, gene expression, migration, and apoptosis. 3. Role of Rho GTPases in mature T cells Binding of the T cell receptor (TCR) to its ligand leads to a complex cascade of biochemical events that eventually results in the activation of transcription factors like AP-1, NFAT, and NFκB, which control the gene expression program characteristic of activated T cells [8]. Engagement of the TCR has been shown to lead to the activation of Rac1 and Rac2 [9]. TCR-induced activation of Rac proteins, in turn, has been implicated in the regulation of MAPKs [10], PI3K [11], PKCθ [12], and calcium responses [11] and thus in the control of the transcriptional activity of AP-1, NFAT, and NF-κB. Studies have shown a complex interplay between Rac proteins and other signaling components. For instance Rac1 can be both upstream and downstream of PI3K activation [13]. An intricate crosstalk also exists between Rac1 and Ras since Rac1 can be both an effector and a regulator of Ras activation. This latter effect is due to the ability of Rac1 to control the translocation of RasGRP1, an activator of Ras [14]. Consistent with a key role for Rac proteins in TCR signaling, CD4+ T cells from Rac2−/− mice exhibit decreases in ERK1/2, p38 activation, and calcium mobilization as well as defective TCRmediated proliferation and diminished IL-2 and IFN-γ production [15,16]. TCR stimulation also leads to the activation of RhoA and blocking RhoA activation has been shown to diminish ERK1/2 activation, calcium responses, and IL-2 production [17]. Furthermore, pharmacologic blockade of ROCKs, key effectors of RhoA, was accompanied by decreased T cell proliferation, diminished production of IL-2 and IFN-γ, and prolonged graft survival in a model of cardiac allograft rejection [18]. Interestingly, recent studies have identified an inhibitor of RhoA, RhoGDI, as a substrate of GRAIL, an E3 ubiquitin ligase enzyme, which plays a key role in the induction of T cell anergy [19]. Expression of GRAIL
Fig. 1. Schematic diagram of Rho GTPase-mediated signaling pathways.
A.B. Pernis / Autoimmunity Reviews 8 (2009) 199–203
interferes with RhoA activation while coexpression of a constitutively active RhoA mutant can overcome the inhibitory effects of GRAIL on IL-2 production suggesting that blocking RhoA activation may be a critical step for the establishment of T cell anergy. The signaling events triggered by TCR engagement are closely interconnected with the reorganization of the actin cytoskeleton [20]. Cytoskeletal remodeling is essential for the formation of the immunological synapse (IS), a specialized interface between CD4+ T cells and antigen-presenting cells (APCs), which is believed to be important for the integration, stabilization, and termination of TCR-generated signaling pathways. Multiple lines of evidence support a role for Rho GTPases in IS assembly. Rac2 deficient T cells exhibit impaired actin polymerization upon TCR stimulation [16]. Furthermore, activation of Rac is critical for the dephosphorylation of ERM (ezrin–radixin– moesin) proteins, an event that leads to decreased T cell rigidity and enables closer contacts between the T cell and the APC [21]. The clustering of lipid rafts at the IS also depends on Rac [22]. In addition to Rac, the activation of Cdc42 is also involved in IS formation and shown to be important for TCR clustering and sustained actin accumulation at the T cell/APC interface [23]. Precise control of cytoskeletal dynamics is fundamental not only for IS assembly but also for the trafficking and recirculation of T cells [20]. T cell migration is a complex process controlled by the engagement of distinct classes of surface receptors, which include integrins and chemokine receptors. Rho GTPases are important components of the signaling cascades mediated by both classes of receptors. Rac and RhoA have been implicated in the proper control of integrin-mediated adhesion and deadhesion [20]. Rho GTPases furthermore participate in chemokine-mediated collapse of microvilli, and in the acquisition of a polarized morphology, processes that are critical for efficient T cell migration [24,25]. Studies have also implicated Rac family members as well as Cdc42 in the regulation of T cell apoptosis. Activation of Rac has been observed after triggering of the Fas receptor in T cells and inhibition of Rac can block Fas-induced apoptosis in these cells [26–28]. This effect is due to a dual ability of Rac to control the expression of FasL and to enhance the sensitivity of T cells to Fas-mediated death [28]. An important role for Rac proteins in T cell apoptosis has recently been supported by genetic studies [28]. Transgenic expression of an activated mutant of Cdc42 in T cells also leads to apoptosis [29] although this may occur in either a Fas-independent or a Fas-dependent manner suggesting that Cdc42 may control T cell apoptosis by multiple mechanisms. 4. Role of Rho GTPase activators in mature T cells Vav proteins are the best-characterized family of GEFs for Rac proteins in T cells (reviewed in [30]). Consistent with this notion, Vav deficiency in T cells leads to defects in many of the pathways in which Rho GTPases have been shown to participate including defects in calcium signaling, MAPK activation, TCR-mediated proliferation, and IL-2 production. Vav deficiency also leads to a plethora of abnormalities in T cell cytoskeletal dynamics, which encompass impairments in clustering of the TCR and of lipid rafts, in the TCR-mediated dephosphorylation of ERM proteins, and in the relocalization of PKCθ to the IS. It is, however, important to note that Vav
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proteins can also act as adapters and therefore not all the signaling and cytoskeletal defects observed in Vav deficient T cells may be directly linked to the ability of these proteins to activate Rho GTPases. Vav proteins are not the only GEFs expressed in mature T cells. Indeed deficiency in DOCK2, a new type of GEF, results in defects in TCR-induced Rac activation as well as in antigeninduced translocation of the TCR and of lipid rafts to the IS [9]. Unlike Vav deficiency, however, the absence of DOCK2 does not affect the localization of PKCθ or LFA1 to the IS and does not impair TCR-signaling pathways suggesting that DOCK2 controls a subset of Rac-mediated cytoskeletal processes. Interestingly, a further analysis of these mice has revealed that they develop excessive TH2 responses [31]. The enhanced skewing toward TH2 differentiation was found to be due to a failure of DOCK2 deficient T cells to properly regulate the intracellular trafficking of the IL-4Rα chain. This led to impaired downregulation of the surface expression of the IL-4Rα chain resulting in sustained IL4 signaling and enhanced autocrine production of IL-4. IBP (IRF-4 Binding Protein [32], also known as Def-6 or SLAT [33,34]) is another novel type of activator for Rho GTPases that is highly expressed in mature T cells. IBP exhibits significant homology to SWAP-70 and is the only member of this class of Rac activators present in the T cell compartment [35]. The ability of IBP to regulate the activation of Rho GTPases is controlled by T cell stimulation [36]. Indeed upon TCR engagement, IBP is rapidly tyrosine phosphorylated, translocates to the immunological synapse, and activates Rac and Cdc42. In keeping with the idea that cells may pair the same Rho GTPase with different GEFs in order to elicit distinct subsets of Rho GTPase-mediated pathways [3], the phenotype of IBP deficient mice is distinct from that observed in Vav or DOCK2 deficient mice. Aging IBP deficient female mice, indeed, spontaneously develop a lupus-like syndrome, characterized by the accumulation of effector CD4+ T cells and markedly aberrant humoral responses [37]. Consistent with the broad role of Rho GTPases in T cell physiology, the lack of IBP affects multiple T cell processes. IBP deficient T cells exhibit an altered pattern of responsiveness to antigenic stimulation marked by hyperresponsiveness to low levels of stimulation and hyporesponsiveness to high levels of stimulation ([37] and unpublished results), which may be mechanistically linked to abnormalities in ERK1/2 activation and IS assembly. Lack of IBP also leads T cells to acquire an aberrant pattern of cytokine production characterized by decreased synthesis of IL-2, IL-4 and IFN-γ [37,38] but enhanced synthesis of IL-17 and IL-21 (unpublished results), cytokines known to control inflammatory and humoral responses and thus autoimmunity [39]. The absence of IBP also results in impaired elimination of antigen-experienced CD4+ T cells [37]. Although it remains to be established whether all the effects observed in the absence of IBP require its capacity to activate Rho GTPases, these studies support the notion that IBP controls a subset of Rho GTPase-mediated pathways that is crucial for the prevention of systemic autoimmunity. 5. Conclusions As outlined above, Rho GTPase-mediated pathways participate in the control of multiple processes that are crucial for the proper regulation of T cell mediated immune responses
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including TCR-mediated signaling and cytoskeletal reorganization, the acquisition of the appropriate T cell effector program, and the elimination of effector T cells. It is thus not surprising that evidence is emerging that inappropriate regulation of Rho GTPase-mediated pathways can play a role in the development of SLE. Although activation of Rho GTPases and their pathways has not been investigated in detail in SLE patients, T cells from these patients exhibit abnormalities in many processes known to be regulated by Rho GTPases including impairments in ERK1/ 2 activation, alterations in ERM phosphorylation, abnormalities in cytoskeletal reorganization and lipid raft dynamics, decreased IL-2 production, and resistance to activation induced cell death [1]. A better understanding of Rho GTPase-mediated pathways in autoimmunity and particularly in SLE may thus provide critical insights into the mechanisms responsible for the development of autoimmunity. Given that modulation of Rho GTPase activation may participate in the anti-inflammatory effects of statins [40] and that targeting this pathway can ameliorate some of the cytoskeletal abnormalities exhibited by SLE T cells [1], this knowledge may also lead to the development of novel therapeutic approaches for the treatment of systemic autoimmunity. Take-home messages • The Rho GTPase family includes Rac1 and Rac2, Cdc42 and RhoA proteins. • Rho GTPases are “molecular switches” that cycle between an inactive, GDP-bound, and an active, GTP-bound, state. • Guanine nucleotide exchange factors (GEFs) are the major class of proteins responsible for the activation of Rho GTPases. • Activation of Rho GTPases is inhibited by two distinct classes of proteins: GAPs (Rho GTPase activating proteins) and RhoGDIs (Rho GDP-dissociation inhibitors). • Rho GTPases have been implicated in the regulation of TCR signaling, T cell cytoskeletal reorganization, T cell migration and T cell apoptosis. • Genetic studies indicate that deficiency in IBP, a novel activator of Rho GTPases, can lead to systemic autoimmunity. References [1] Crispin JC, Kyttaris V, Juang YT, Tsokos GC. Systemic lupus erythematosus: new molecular targets. Ann Rheum Dis Nov 2007;66(Suppl 3):iii65–9. [2] Bustelo XR, Sauzeau V, Berenjeno IM. GTP-binding proteins of the Rho/ Rac family: regulation, effectors and functions in vivo. Bioessays Apr 2007;29(4):356–70. [3] Schmidt A, Hall A. Guanine nucleotide exchange factors for Rho GTPases: turning on the switch. Genes Dev Jul 1 2002;16(13):1587–609. [4] Shinohara M, Terada Y, Iwamatsu A, Shihora A, Mochizuki N, Higuchi M, et al. SWAP-70 is a guanine-nucleotide-exchange factor that mediates signalling of membrane ruffling. Nature 2002;416:759–63. [5] Cote JF, Vuori K. GEF what? Dock180 and related proteins help Rac to polarize cells in new ways. Trends Cell Biol Aug 2007;17(8):383–93. [6] Moon SY, Zheng Y. Rho GTPase-activating proteins in cell regulation. Trends Cell Biol Jan 2003;13(1):13–22. [7] DerMardirossian C, Bokoch GM. GDIs: central regulatory molecules in Rho GTPase activation. Trends Cell Biol Jul 2005;15(7):356–63. [8] Kane LP, Lin J, Weiss A. Signal transduction by the TCR for antigen. Curr Opin Immunol Jun 2000;12(3):242–9. [9] Sanui T, Inayoshi A, Noda M, Iwata E, Oike M, Sasazuki T. DOCK2 is essential for antigen-induced translocation of TCR and lipid rafts, but not PKC-theta and LFA-1, in T cells. Immunity Jul 2003;19(1):119–29. [10] Jacinto E, Werlen G, Karin M. Cooperation between Syk and Rac1 leads to synergistic JNK activation in T lymphocytes. Immunity Jan 1998;8(1):31–41.
[11] Arrieumerlou C, Randriamampita C, Bismuth G, Trautmann A. Rac is involved in early TCR signaling. J Immunol Sep 15 2000;165(6):3182–9. [12] Villalba M, Coudronniere N, Deckert M, Teixeiro E, Mas P, Altman A. A novel functional interaction between Vav and PKCtheta is required for TCR-induced T cell activation. Immunity Feb 2000;12(2):151–60. [13] Genot EM, Arrieumerlou C, Ku G, Burgering BM, Weiss A, Kramer IM. The T-cell receptor regulates Akt (protein kinase B) via a pathway involving Rac1 and phosphatidylinositide 3-kinase. Mol Cell Biol Aug 2000;20 (15):5469–78. [14] Zugaza JL, Caloca MJ, Bustelo XR. Inverted signaling hierarchy between RAS and RAC in T-lymphocytes. Oncogene Jul 29 2004;23(34):5823–33. [15] Li B, Yu H, Zheng W, Voll R, Na S, Roberts AW. Role of the guanosine triphosphatase Rac2 in T helper 1 cell differentiation. Science Jun 23 2000;288(5474):2219–22. [16] Yu H, Leitenberg D, Li B, Flavell RA. Deficiency of small GTPase Rac2 affects T cell activation. J Exp Med Oct 1 2001;194(7):915–26. [17] Angkachatchai V, Finkel TH. ADP-ribosylation of rho by C3 ribosyltransferase inhibits IL-2 production and sustained calcium influx in activated T cells. J Immunol Oct 1 1999;163(7):3819–25. [18] Tharaux PL, Bukoski RC, Rocha PN, Crowley SD, Ruiz P, Nataraj C, et al. Rho kinase promotes alloimmune responses by regulating the proliferation and structure of T cells. J Immunol Jul 1 2003;171(1):96–105. [19] Su L, Lineberry N, Huh Y, Soares L, Fathman CG. A novel E3 ubiquitin ligase substrate screen identifies Rho guanine dissociation inhibitor as a substrate of gene related to anergy in lymphocytes. J Immunol Dec 1 2006;177(11):7559–66. [20] Vicente-Manzanares M, Sanchez-Madrid F. Role of the cytoskeleton during leukocyte responses. Nat Rev Immunol Feb 2004;4(2):110–22. [21] Faure S, Salazar-Fontana LI, Semichon M, Tybulewicz VL, Bismuth G, Trautmann A, et al. ERM proteins regulate cytoskeleton relaxation promoting T cell-APC conjugation. Nat Immunol Mar 2004;5(3):272–9. [22] Villalba M, Bi K, Rodriguez F, Tanaka Y, Schoenberger S, Altman A. Vav1/ Rac-dependent actin cytoskeleton reorganization is required for lipid raft clustering in T cells. J Cell Biol Oct 29 2001;155(3):331–8. [23] Tskvitaria-Fuller I, Seth A, Mistry N, Gu H, Rosen MK, Wulfing C. Specific patterns of Cdc42 activity are related to distinct elements of T cell polarization. J Immunol Aug 1 2006;177(3):1708–20. [24] Lee JH, Katakai T, Hara T, Gonda H, Sugai M, Shimizu A. Roles of p-ERM and Rho-ROCK signaling in lymphocyte polarity and uropod formation. J Cell Biol Oct 25 2004;167(2):327–37. [25] Nijhara R, van Hennik PB, Gignac ML, Kruhlak MJ, Hordijk PL, Delon J, et al. Rac1 mediates collapse of microvilli on chemokine-activated T lymphocytes. J Immunol Oct 15 2004;173(8):4985–93. [26] Brenner B, Koppenhoefer U, Weinstock C, Linderkamp O, Lang F, Gulbins E. Fas- or ceramide-induced apoptosis is mediated by a Rac1-regulated activation of Jun N- terminal kinase/p38 kinases and GADD153. J Biol Chem Aug 29 1997;272(35):22173–81. [27] Gulbins E, Coggeshall KM, Brenner B, Schlottmann K, Linderkamp O, Lang F. Fas-induced apoptosis is mediated by activation of a Ras and Rac protein-regulated signaling pathway. J Biol Chem Oct 18 1996;271 (42):26389–94. [28] Ramaswamy M, Dumont C, Cruz AC, Muppidi JR, Gomez TS, Billadeau DD, et al. Cutting edge: Rac GTPases sensitize activated T cells to die via Fas. J Immunol Nov 15 2007;179(10):6384–8. [29] Na S, Li B, Grewal IS, Enslen H, Davis RJ, Hanke JH, et al. Expression of activated CDC42 induces T cell apoptosis in thymus and peripheral lymph organs via different pathways. Oncogene Dec 23 1999;18 (56):7966–74. [30] Tybulewicz VL. Vav-family proteins in T-cell signalling. Curr Opin Immunol Jun 2005;17(3):267–74. [31] Tanaka Y, Hamano S, Gotoh K, Murata Y, Kunisaki Y, Nishikimi A, et al. T helper type 2 differentiation and intracellular trafficking of the interleukin 4 receptor-alpha subunit controlled by the Rac activator Dock2. Nat Immunol Oct 2007;8(10):1067–75. [32] Gupta S, Lee A, Hu C, Fanzo J, Goldberg I, Cattoretti G, et al. Molecular cloning of IBP, a SWAP-70 homologous GEF, which is highly expressed in the immune system. Hum Immunol Apr 2003;64(4):389–401. [33] Hotfilder M, Baxendale S, Cross MA, Sablitzky F. Def-2, -3, -6, -8, novel mouse genes differentially expressed in the hematopoietic system. Br J Haematol 1999;106:335–44. [34] Tanaka Y, Bi K, Kitamura R, Hong S, Altman Y, Matsumoto A, et al. SWAP70- like adapter of T cells, an adapter protein that regulates early TCRinitiated signaling in Th2 lineage cells. Immunity 2003;18:403–14. [35] Borggrefe T, Masat L, Wabl M, Riwar B, Cattoretti G, Jessberger R. Cellular, intracellular, and developmental expression patterns of murine SWAP-70. Eur J Immunol Jun 1999;29(6):1812–22. [36] Gupta S, Fanzo JC, Hu C, Cox D, Jang SY, Lee AE, et al. T cell receptor engagement leads to the recruitment of IBP, a novel guanine nucleotide exchange factor, to the immunological synapse. J Biol Chem Oct 31 2003;278(44):43541–9.
A.B. Pernis / Autoimmunity Reviews 8 (2009) 199–203 [37] Fanzo JC, Yang W, Jang SY, Gupta S, Chen Q, Siddiq A, et al. Loss of IRF-4binding protein leads to the spontaneous development of systemic autoimmunity. J Clin Invest Mar 2006;116(3):703–14. [38] Becart S, Charvet C, Canonigo Balancio AJ, De Trez C, Tanaka Y, Duan W, et al. SLAT regulates Th1 and Th2 inflammatory responses by controlling Ca2+/NFAT signaling. J Clin Invest Aug 2007;117(8):2164–75.
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Anti-alpha-fodrin in Sjogren's syndrome Alpha-fodrin is a well known antigen related to Sjogren's syndrome pathophysiology. He et al. (Arthritis Res Ther 2008;10:R44) have speculated if the nasal immunization with alpha-fodrin might be effective in this disease. They have immunized NOD mice with 1 to 10 mcg every other day and compared with controls. The authors found that the appearance of anti-alpha-fodrin and anti-type 3 muscarinic acetylcholine receptor peptide antibodies was delayed and the titers of these antibodies were lower in the immunized mice with alpha-fodrin than controls. In addition, the appearance of antinuclear antibodies had decreased in alpha-fodrin immunized mice in comparison to those immunized with saline. Levels of interferon gamma were also lower in immunized group, however interleukin-10 levels were similar in both groups of animals. Interestingly, the number of regulatory T cells (Foxp3+ CD4+CD25+) was higher in alpha-fodrin group. The histopathology studies showed a diminishing of the number of lymphocytes and alpha-fodrin expression. This study has shown that the nasal tolerance with alpha-fodrin may have a role in the treatment of experimental Sjogren's syndrome.
Interleukin-33 and antigen-induced arthritis Interleukin-33 is an inflammatory cytokine linked to interleukin-1 family. In an experimental study, Xu et al. (Proc Nat Acad Sci 2008;105:10913-8) have demonstrated that mice lacking interleukin-33 receptor, have developed attenuated collagen-induced arthritis, and also a significant reduction of the synthesis of interleukin-17, TNF, interferon gamma and immunoglobulins. In addition, the injection of interleukin-33 in wild mice led to an exacerbated collagen-induced arthritis, but it was not observed in interleukin-33 receptor deficient animals. The authors could also demonstrate that this proinflammatory property of interleukin-33 is mediated by mast cells. In fact, transferring mastocytes from wild mice to interleukin-33 deficient rodents after interleukin-33 infusion. This study suggests that interleukin-33 has a role in inflammatory process of antigen-induced arthritis and it seems to be mediated via mast cells.
Roles of CD4+CD25 high FoxP3+ Tregs in lymphomas and tumors are complex CD4+CD25 (high) FoxP3+ T regulatory (Tregs) cells play an important role in the maintenance of immunological self-tolerance by suppressing both autoimmune and anti-tumor responses. The current model suggests that epithelial tumor cells recruit Tregs to inhibit anti-tumor immunity in the tumor microenvironment, which thus limits the efficiency of anti-tumor immune responses and immunotherapy. However, recent findings on Tregs in lymphomas have complicated this working model. The biopsy specimens of some lymphomas have significantly higher percentages of Tregs than that in tumor-free lymph nodes and normal peripheral mononuclear cells. Higher Tregs numbers in these lymphomas predict improved survival and prognosis of patients. In this brief review, Ke X. et al. (Frontiers in Bioscience 2008; 13: 3986-4001) summarize the progress in understanding the role of Tregs in lymphomas and other tumors and define the potentials of Tregs-based immunotherapeutics.
Contents lists available at ScienceDirect
Autoimmunity Reviews j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / a u t r ev
Rho GTPase-mediated pathways in mature CD4+ T cells☆ Alessandra B. Pernis ⁎ Department of Medicine, Columbia University, 630 West 168th Street, New York, NY 10032, United States
a r t i c l e
i n f o
Available online 22 August 2008 Keywords: Systemic Lupus Erythematosus (SLE) Guanine nucleotide exchange factor (GEF) Rho GTPase activating protein (GAP) Rho GDP-dissociation inhibitor (RhoGDI) IRF-4 Binding Protein (IBP)
a b s t r a c t Effective immune responses require the appropriate activation and differentiation of peripheral CD4+ Tcells. These processes need to be followed by the timely elimination of the responding Tcells in order to restore T cell homeostasis. Defects in the appropriate regulation of T cell activation, expansion, and survival underlie the pathogenesis of many autoimmune disorders including SLE. The molecular machinery employed by T cells to properly control these processes and prevent the onset of autoimmunity has not been fully elucidated. Rho GTPases (which include the Rac, Cdc42, and Rho subfamilies) are molecular switches that control a wide range of cellular processes. Their fundamental role in biology is due to their ability to regulate both cytoskeletal dynamics and a large number of signal transduction pathways. Activation of Rho GTPases is now recognized as a key event in the coordination of immune responses and, particularly, in the activation of T cells. In this review, we will first provide an overview of the role of Rho GTPase-mediated pathways in mature CD4+ T cells and then we will discuss recent studies, which suggest that deregulation of these pathways may play a role in the pathogenesis of SLE. © 2008 Published by Elsevier B.V.
Contents 1. Introduction . . . . . . . . . . . . . . . . . . 2. Rho GTPase-mediated pathways: the basic scheme 3. Role of Rho GTPases in mature T cells . . . . . . 4. Role of Rho GTPase activators in mature T cells . . 5. Conclusions . . . . . . . . . . . . . . . . . . . Take-home messages . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction Defects in the appropriate regulation of T cell activation, expansion, and survival play a crucial role in the pathogenesis of Systemic Lupus Erythematosus (SLE) [1]. The molecular machinery employed by the immune system to prevent the development of autoimmune disorders like SLE is not fully understood. Rho GTPases are molecular switches that control a wide range of
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biological processes due to their capacity to regulate both signaling pathways as well as cytoskeletal reorganization [2]. In this review, which is part of a series on signaling pathways in SLE, we will provide an overview of the role of Rho GTPase-mediated pathways in mature T lymphocytes, and discuss recent studies, which suggest that deregulation of these pathways may participate in the pathogenesis of SLE. 2. Rho GTPase-mediated pathways: the basic scheme
☆ Research support is provided by NIH grant R01 HL-62215, the Lupus Research Institute, and the Alliance for Lupus Research. ⁎ Tel.: +212 305 3763; fax: +212 305 4478. E-mail address: [email protected]. 1568-9972/$ – see front matter © 2008 Published by Elsevier B.V. doi:10.1016/j.autrev.2008.07.044
The Rho family of GTPases is a large family of proteins, which includes RhoA, Rac1, Rac2, and Cdc42 [2]. Like other small GTPases, Rho GTPases behave like “molecular switches”
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that cycle between an inactive, GDP-bound, and an active, GTPbound, state (Fig. 1). The major class of proteins responsible for the activation of Rho GTPases is the Dbl family of guanine nucleotide exchange factors (GEFs) [3]. These GEFs catalyze the release of GDP leading to the formation of active GTP-bound Rho GTPases. Members of the Dbl family are characterized by the presence of a catalytic Dbl-homology (DH) domain followed by a C-terminal PH domain necessary for proper intracellular localization and function. Recent studies have revealed the existence of additional classes of activators for Rho GTPases. In particular, SWAP-70 was found to be a novel type of activator for Rac, in which a DH-like domain is flanked at its N-terminus, rather than at its C-terminus, by a PH domain [4]. A new family of GEFs characterized by the presence of a different domain termed the Dock homology region (DHR)-2 domain has also been identified [5]. The ability of GEFs to activate Rho GTPases is itself strictly regulated since GEFs normally exist in an inactive state and become activated in response to extracellular stimuli via either phosphorylation, changes in subcellular localization, or interaction with cofactors. A number of inhibitory systems are also in place to ensure that activation of Rho GTPases is tightly regulated. Proteins called GAPs (Rho GTPase activating proteins) inhibit the activation of Rho GTPases by increasing the weak intrinsic GTPase activity of Rho GTPases thus promoting their conversion to an inactive GDP-bound state [6]. A different family of molecules called RhoGDIs (Rho GDP-dissociation inhibitors) instead interferes with the activation of Rho GTPases by preventing the dissociation of GDP and by blocking their recruitment to the plasma membrane, a step that is necessary for the interaction of Rho GTPases with GEFs [7]. Once they become activated Rho GTPases control cytoskeletal dynamics as well as numerous signaling pathways due to their capacity to bind to and activate a large number of downstream effector molecules, which include serine/threonine kinases, lipid kinases, and adaptors [2]. Rac and Cdc42 can bind to many of the same effectors like the PAK kinases. RhoA instead usually targets a different set of effectors, like the Rhoassociated coiled-coil-containing protein kinases (ROCK-I and
ROCK-II) and thus often regulates distinct signaling and cytoskeletal events. Due to their ability to target multiple pathways, Rho GTPases have been implicated in the control of a wide range of biological processes such as proliferation, gene expression, migration, and apoptosis. 3. Role of Rho GTPases in mature T cells Binding of the T cell receptor (TCR) to its ligand leads to a complex cascade of biochemical events that eventually results in the activation of transcription factors like AP-1, NFAT, and NFκB, which control the gene expression program characteristic of activated T cells [8]. Engagement of the TCR has been shown to lead to the activation of Rac1 and Rac2 [9]. TCR-induced activation of Rac proteins, in turn, has been implicated in the regulation of MAPKs [10], PI3K [11], PKCθ [12], and calcium responses [11] and thus in the control of the transcriptional activity of AP-1, NFAT, and NF-κB. Studies have shown a complex interplay between Rac proteins and other signaling components. For instance Rac1 can be both upstream and downstream of PI3K activation [13]. An intricate crosstalk also exists between Rac1 and Ras since Rac1 can be both an effector and a regulator of Ras activation. This latter effect is due to the ability of Rac1 to control the translocation of RasGRP1, an activator of Ras [14]. Consistent with a key role for Rac proteins in TCR signaling, CD4+ T cells from Rac2−/− mice exhibit decreases in ERK1/2, p38 activation, and calcium mobilization as well as defective TCRmediated proliferation and diminished IL-2 and IFN-γ production [15,16]. TCR stimulation also leads to the activation of RhoA and blocking RhoA activation has been shown to diminish ERK1/2 activation, calcium responses, and IL-2 production [17]. Furthermore, pharmacologic blockade of ROCKs, key effectors of RhoA, was accompanied by decreased T cell proliferation, diminished production of IL-2 and IFN-γ, and prolonged graft survival in a model of cardiac allograft rejection [18]. Interestingly, recent studies have identified an inhibitor of RhoA, RhoGDI, as a substrate of GRAIL, an E3 ubiquitin ligase enzyme, which plays a key role in the induction of T cell anergy [19]. Expression of GRAIL
Fig. 1. Schematic diagram of Rho GTPase-mediated signaling pathways.
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interferes with RhoA activation while coexpression of a constitutively active RhoA mutant can overcome the inhibitory effects of GRAIL on IL-2 production suggesting that blocking RhoA activation may be a critical step for the establishment of T cell anergy. The signaling events triggered by TCR engagement are closely interconnected with the reorganization of the actin cytoskeleton [20]. Cytoskeletal remodeling is essential for the formation of the immunological synapse (IS), a specialized interface between CD4+ T cells and antigen-presenting cells (APCs), which is believed to be important for the integration, stabilization, and termination of TCR-generated signaling pathways. Multiple lines of evidence support a role for Rho GTPases in IS assembly. Rac2 deficient T cells exhibit impaired actin polymerization upon TCR stimulation [16]. Furthermore, activation of Rac is critical for the dephosphorylation of ERM (ezrin–radixin– moesin) proteins, an event that leads to decreased T cell rigidity and enables closer contacts between the T cell and the APC [21]. The clustering of lipid rafts at the IS also depends on Rac [22]. In addition to Rac, the activation of Cdc42 is also involved in IS formation and shown to be important for TCR clustering and sustained actin accumulation at the T cell/APC interface [23]. Precise control of cytoskeletal dynamics is fundamental not only for IS assembly but also for the trafficking and recirculation of T cells [20]. T cell migration is a complex process controlled by the engagement of distinct classes of surface receptors, which include integrins and chemokine receptors. Rho GTPases are important components of the signaling cascades mediated by both classes of receptors. Rac and RhoA have been implicated in the proper control of integrin-mediated adhesion and deadhesion [20]. Rho GTPases furthermore participate in chemokine-mediated collapse of microvilli, and in the acquisition of a polarized morphology, processes that are critical for efficient T cell migration [24,25]. Studies have also implicated Rac family members as well as Cdc42 in the regulation of T cell apoptosis. Activation of Rac has been observed after triggering of the Fas receptor in T cells and inhibition of Rac can block Fas-induced apoptosis in these cells [26–28]. This effect is due to a dual ability of Rac to control the expression of FasL and to enhance the sensitivity of T cells to Fas-mediated death [28]. An important role for Rac proteins in T cell apoptosis has recently been supported by genetic studies [28]. Transgenic expression of an activated mutant of Cdc42 in T cells also leads to apoptosis [29] although this may occur in either a Fas-independent or a Fas-dependent manner suggesting that Cdc42 may control T cell apoptosis by multiple mechanisms. 4. Role of Rho GTPase activators in mature T cells Vav proteins are the best-characterized family of GEFs for Rac proteins in T cells (reviewed in [30]). Consistent with this notion, Vav deficiency in T cells leads to defects in many of the pathways in which Rho GTPases have been shown to participate including defects in calcium signaling, MAPK activation, TCR-mediated proliferation, and IL-2 production. Vav deficiency also leads to a plethora of abnormalities in T cell cytoskeletal dynamics, which encompass impairments in clustering of the TCR and of lipid rafts, in the TCR-mediated dephosphorylation of ERM proteins, and in the relocalization of PKCθ to the IS. It is, however, important to note that Vav
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proteins can also act as adapters and therefore not all the signaling and cytoskeletal defects observed in Vav deficient T cells may be directly linked to the ability of these proteins to activate Rho GTPases. Vav proteins are not the only GEFs expressed in mature T cells. Indeed deficiency in DOCK2, a new type of GEF, results in defects in TCR-induced Rac activation as well as in antigeninduced translocation of the TCR and of lipid rafts to the IS [9]. Unlike Vav deficiency, however, the absence of DOCK2 does not affect the localization of PKCθ or LFA1 to the IS and does not impair TCR-signaling pathways suggesting that DOCK2 controls a subset of Rac-mediated cytoskeletal processes. Interestingly, a further analysis of these mice has revealed that they develop excessive TH2 responses [31]. The enhanced skewing toward TH2 differentiation was found to be due to a failure of DOCK2 deficient T cells to properly regulate the intracellular trafficking of the IL-4Rα chain. This led to impaired downregulation of the surface expression of the IL-4Rα chain resulting in sustained IL4 signaling and enhanced autocrine production of IL-4. IBP (IRF-4 Binding Protein [32], also known as Def-6 or SLAT [33,34]) is another novel type of activator for Rho GTPases that is highly expressed in mature T cells. IBP exhibits significant homology to SWAP-70 and is the only member of this class of Rac activators present in the T cell compartment [35]. The ability of IBP to regulate the activation of Rho GTPases is controlled by T cell stimulation [36]. Indeed upon TCR engagement, IBP is rapidly tyrosine phosphorylated, translocates to the immunological synapse, and activates Rac and Cdc42. In keeping with the idea that cells may pair the same Rho GTPase with different GEFs in order to elicit distinct subsets of Rho GTPase-mediated pathways [3], the phenotype of IBP deficient mice is distinct from that observed in Vav or DOCK2 deficient mice. Aging IBP deficient female mice, indeed, spontaneously develop a lupus-like syndrome, characterized by the accumulation of effector CD4+ T cells and markedly aberrant humoral responses [37]. Consistent with the broad role of Rho GTPases in T cell physiology, the lack of IBP affects multiple T cell processes. IBP deficient T cells exhibit an altered pattern of responsiveness to antigenic stimulation marked by hyperresponsiveness to low levels of stimulation and hyporesponsiveness to high levels of stimulation ([37] and unpublished results), which may be mechanistically linked to abnormalities in ERK1/2 activation and IS assembly. Lack of IBP also leads T cells to acquire an aberrant pattern of cytokine production characterized by decreased synthesis of IL-2, IL-4 and IFN-γ [37,38] but enhanced synthesis of IL-17 and IL-21 (unpublished results), cytokines known to control inflammatory and humoral responses and thus autoimmunity [39]. The absence of IBP also results in impaired elimination of antigen-experienced CD4+ T cells [37]. Although it remains to be established whether all the effects observed in the absence of IBP require its capacity to activate Rho GTPases, these studies support the notion that IBP controls a subset of Rho GTPase-mediated pathways that is crucial for the prevention of systemic autoimmunity. 5. Conclusions As outlined above, Rho GTPase-mediated pathways participate in the control of multiple processes that are crucial for the proper regulation of T cell mediated immune responses
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including TCR-mediated signaling and cytoskeletal reorganization, the acquisition of the appropriate T cell effector program, and the elimination of effector T cells. It is thus not surprising that evidence is emerging that inappropriate regulation of Rho GTPase-mediated pathways can play a role in the development of SLE. Although activation of Rho GTPases and their pathways has not been investigated in detail in SLE patients, T cells from these patients exhibit abnormalities in many processes known to be regulated by Rho GTPases including impairments in ERK1/ 2 activation, alterations in ERM phosphorylation, abnormalities in cytoskeletal reorganization and lipid raft dynamics, decreased IL-2 production, and resistance to activation induced cell death [1]. A better understanding of Rho GTPase-mediated pathways in autoimmunity and particularly in SLE may thus provide critical insights into the mechanisms responsible for the development of autoimmunity. Given that modulation of Rho GTPase activation may participate in the anti-inflammatory effects of statins [40] and that targeting this pathway can ameliorate some of the cytoskeletal abnormalities exhibited by SLE T cells [1], this knowledge may also lead to the development of novel therapeutic approaches for the treatment of systemic autoimmunity. Take-home messages • The Rho GTPase family includes Rac1 and Rac2, Cdc42 and RhoA proteins. • Rho GTPases are “molecular switches” that cycle between an inactive, GDP-bound, and an active, GTP-bound, state. • Guanine nucleotide exchange factors (GEFs) are the major class of proteins responsible for the activation of Rho GTPases. • Activation of Rho GTPases is inhibited by two distinct classes of proteins: GAPs (Rho GTPase activating proteins) and RhoGDIs (Rho GDP-dissociation inhibitors). • Rho GTPases have been implicated in the regulation of TCR signaling, T cell cytoskeletal reorganization, T cell migration and T cell apoptosis. • Genetic studies indicate that deficiency in IBP, a novel activator of Rho GTPases, can lead to systemic autoimmunity. References [1] Crispin JC, Kyttaris V, Juang YT, Tsokos GC. Systemic lupus erythematosus: new molecular targets. Ann Rheum Dis Nov 2007;66(Suppl 3):iii65–9. [2] Bustelo XR, Sauzeau V, Berenjeno IM. GTP-binding proteins of the Rho/ Rac family: regulation, effectors and functions in vivo. Bioessays Apr 2007;29(4):356–70. [3] Schmidt A, Hall A. Guanine nucleotide exchange factors for Rho GTPases: turning on the switch. Genes Dev Jul 1 2002;16(13):1587–609. [4] Shinohara M, Terada Y, Iwamatsu A, Shihora A, Mochizuki N, Higuchi M, et al. SWAP-70 is a guanine-nucleotide-exchange factor that mediates signalling of membrane ruffling. Nature 2002;416:759–63. [5] Cote JF, Vuori K. GEF what? Dock180 and related proteins help Rac to polarize cells in new ways. Trends Cell Biol Aug 2007;17(8):383–93. [6] Moon SY, Zheng Y. Rho GTPase-activating proteins in cell regulation. Trends Cell Biol Jan 2003;13(1):13–22. [7] DerMardirossian C, Bokoch GM. GDIs: central regulatory molecules in Rho GTPase activation. Trends Cell Biol Jul 2005;15(7):356–63. [8] Kane LP, Lin J, Weiss A. Signal transduction by the TCR for antigen. Curr Opin Immunol Jun 2000;12(3):242–9. [9] Sanui T, Inayoshi A, Noda M, Iwata E, Oike M, Sasazuki T. DOCK2 is essential for antigen-induced translocation of TCR and lipid rafts, but not PKC-theta and LFA-1, in T cells. Immunity Jul 2003;19(1):119–29. [10] Jacinto E, Werlen G, Karin M. Cooperation between Syk and Rac1 leads to synergistic JNK activation in T lymphocytes. Immunity Jan 1998;8(1):31–41.
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Anti-alpha-fodrin in Sjogren's syndrome Alpha-fodrin is a well known antigen related to Sjogren's syndrome pathophysiology. He et al. (Arthritis Res Ther 2008;10:R44) have speculated if the nasal immunization with alpha-fodrin might be effective in this disease. They have immunized NOD mice with 1 to 10 mcg every other day and compared with controls. The authors found that the appearance of anti-alpha-fodrin and anti-type 3 muscarinic acetylcholine receptor peptide antibodies was delayed and the titers of these antibodies were lower in the immunized mice with alpha-fodrin than controls. In addition, the appearance of antinuclear antibodies had decreased in alpha-fodrin immunized mice in comparison to those immunized with saline. Levels of interferon gamma were also lower in immunized group, however interleukin-10 levels were similar in both groups of animals. Interestingly, the number of regulatory T cells (Foxp3+ CD4+CD25+) was higher in alpha-fodrin group. The histopathology studies showed a diminishing of the number of lymphocytes and alpha-fodrin expression. This study has shown that the nasal tolerance with alpha-fodrin may have a role in the treatment of experimental Sjogren's syndrome.
Interleukin-33 and antigen-induced arthritis Interleukin-33 is an inflammatory cytokine linked to interleukin-1 family. In an experimental study, Xu et al. (Proc Nat Acad Sci 2008;105:10913-8) have demonstrated that mice lacking interleukin-33 receptor, have developed attenuated collagen-induced arthritis, and also a significant reduction of the synthesis of interleukin-17, TNF, interferon gamma and immunoglobulins. In addition, the injection of interleukin-33 in wild mice led to an exacerbated collagen-induced arthritis, but it was not observed in interleukin-33 receptor deficient animals. The authors could also demonstrate that this proinflammatory property of interleukin-33 is mediated by mast cells. In fact, transferring mastocytes from wild mice to interleukin-33 deficient rodents after interleukin-33 infusion. This study suggests that interleukin-33 has a role in inflammatory process of antigen-induced arthritis and it seems to be mediated via mast cells.
Roles of CD4+CD25 high FoxP3+ Tregs in lymphomas and tumors are complex CD4+CD25 (high) FoxP3+ T regulatory (Tregs) cells play an important role in the maintenance of immunological self-tolerance by suppressing both autoimmune and anti-tumor responses. The current model suggests that epithelial tumor cells recruit Tregs to inhibit anti-tumor immunity in the tumor microenvironment, which thus limits the efficiency of anti-tumor immune responses and immunotherapy. However, recent findings on Tregs in lymphomas have complicated this working model. The biopsy specimens of some lymphomas have significantly higher percentages of Tregs than that in tumor-free lymph nodes and normal peripheral mononuclear cells. Higher Tregs numbers in these lymphomas predict improved survival and prognosis of patients. In this brief review, Ke X. et al. (Frontiers in Bioscience 2008; 13: 3986-4001) summarize the progress in understanding the role of Tregs in lymphomas and other tumors and define the potentials of Tregs-based immunotherapeutics.