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Rheumatology Advance Access originally published online on June 24, 2007
Rheumatology 2007 46(10):1525-1530; doi:10.1093/rheumatology/kem154
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© The Author 2007. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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Altered signal transduction in SLE T cells

K. Tenbrock1, Y.-T. Juang2, V. C. Kyttaris2 and G. C. Tsokos2

1Department of Pediatrics, Division of Rheumatology, University Hospital Muenster, 48145 Muenster, Germany and 2Division of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.

Correspondence to: Klaus Tenbrock, University of Münster, Department of Pediatrics, Division of Rheumatology, Institute of Experimental Dermatology, Röntgenstr. 21 D-48149 Münster, Germany. E-mail: ktenbroc{at}uni-muenster.de


   Abstract
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 Abstract
Introduction
 Methods
 Conclusions and future...
 References
 
T cells from patients with systemic lupus erythematosus display numerous signalling abnormalities. The T cell receptor complex is rewired with the common FcR{gamma} chain replacing the CD3 {zeta} chain while the T cell surface membrane lipid rafts are aggregated. These two aberrations result in enhanced early signalling events and altered downstream signalling events. These are in turn responsible for an altered expression of cytokines such as interleukin-6 (IL-6), IL-10, IL-2, IFNy and CD40 ligand. While some of these abnormalities explain the enhanced ability of T cells to help B cells to produce autoantibodies, decreased IL-2 production results in enhanced susceptibility to infections, reduced activation-induced cell death and prolonged survival of autoreactive T cells, which promote help to autoreactive B cells.

KEY WORDS: lupus, CREM, CamKIV, Elf-1, NFAT, AP-1


   Introduction
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 Abstract
 Introduction
Methods
 Conclusions and future...
 References
 
Systemic lupus erythematosus (SLE) is a complex autoimmune disease of unknown origin affecting virtually every organ in the human body. A strong genetic predisposition along with environmental and hormonal factors results in the expression of disease pathology. At the immunopathogenesis level, loss of tolerance against multiple antigens, primarily of nuclear origin results in the generation of autoreactive T and B cells and the production of a multitude of autoantibodies [1].

Although SLE is recognized primarily as a B-cell disease with the production of pathogenic autoantibodies, the contribution of T cells to the expression of immunopathology is not questionable. Activated T cells express CD40 ligand (CD40L) and support B cells to differentiate into plasma cells through the engagement of CD40 present on the surface of B cells [2]. T cells from SLE patients display a memory phenotype with relatively low numbers of naïve and suppressor inducer T cells [3, 4]. Furthermore, regulatory T cells are reduced in patients with SLE [5, 6]. IFNy and IL-2 production is reduced in sera of SLE patients, while IL-6 and IL-10 are produced at enhanced levels [7–10]. Decreased IL-2 production results in a reduced activation-induced cell death (AICD) and the persistence of autoreactive and memory type T cells. Furthermore IL-2 is a critical cytokine for the generation and persistence of regulatory T cells [11]. The increased susceptibility to infections and persistence of autoreactive T and B cells, invariably seen in SLE patients, can be at least, in part, explained on the basis of these signalling abnormalities, which will be discussed subsequently.


   Methods
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 Abstract
 Introduction
 Methods
Conclusions and future...
 References
 
Rewiring of the T cell receptor (TCR) in SLE T cells
TCR is important for antigen-recognition and signal transduction. Its integrity is vital for the induction of an efficient immune response. The TCR {zeta} chain is a critical component of the TCR complex, since it plays a key role in receptor assembly, expression and signalling [12]. The TCR {zeta} chain is unique in that it contains more (three) phosphorylation motifs (ITAMs) than other CD3 components and therefore is considered critical in relaying extracellular signals inwardly [13].

We have reported that patients with SLE display defective expression of TCR {zeta} chain protein and mRNA [14]. A decrease of the TCR {zeta} chain can also be found in other chronic diseases like cancer and in rheumatoid arthritis, however, down-regulation of the TCR {zeta} chain occurs at the side of inflammation in rheumatoid arthritis, which means in the synoival fluid of the inflamed joint, while the expression of the TCR {zeta} chain is not reduced in the peripheral blood [15]. Similar observations were made in tumour-infiltrating lymphocytes, while the lymphocytes in the peripheral blood of tumour-bearing hosts only showed abnormalities in the late stage of disease. Additionally, in chronic infections such as leprosy, a down-regulation of the TCR {zeta} chain has been observed as well [16], however, this does not result in SLE-similar T-cellular phenotype with an enhanced Ca-influx, which will be discussed subsequently [17].

Several mechanisms contribute to the decreased expression of the TCR {zeta} chain in SLE T cells. These include decreased TCR {zeta} promoter activity, decreased mRNA stability and enhanced degradation of TCR {zeta}. The most important transcription factor for the regulation of the TCR {zeta} chain expression is Elf-1. Binding of Elf-1 to the promoter was proposed to account exclusively for the regulation of the transcription rate of the TCR {zeta} gene in normal T cells [18]. Therefore, we investigated the expression and DNA binding of Elf-1 in T cells from patients with SLE. In the course of these studies, we identified two groups of SLE patients with distinct abnormalities in the expression and function of Elf-1. In the first group of patients, T cells did not produce the 98 kDa form of Elf-1, the form that we [19] and others had determined to represent the DNA-binding form of Elf-1. In the second group of patients, T cells form the 98 kDa form but it failed to bind DNA because it was not properly phosphorylated [19, 20]. Simultaneously, we realized that a defect in the production of DNA-binding Elf-1 could not entirely explain the deficient TCR {zeta} promoter activity in SLE T cells. We established that the transcriptional repressor CREM{alpha} is involved in the transcriptional repression of the TCR {zeta} promoter as well [21]. CREM{alpha} will be discussed in detail aubsequently.

In addition to the altered promoter activity, SLE T cells display significantly high levels of TCR {zeta} mRNA with the alternatively spliced 3' untranslated region (AS) 3' UTR form, which is derived by splice deletion of nucleotides 672–1233 of the TCR {zeta} transcript. The stability of TCR {zeta} mRNA with an AS 3' UTR is low compared with TCR {zeta} mRNA with wild-type 3' UTR. Two adenosine-uridine-rich sequence elements (AREs), defined by the splice-deleted 3' UTR region are responsible for securing TCR {zeta} mRNA stability and translation. In SLE T cells, these AREs are absent and therefore, the TCR {zeta} chain mRNA is less stable [22, 23].

Furthermore, SLE T cells show an enhanced expression and activity of caspase-3. Treatment of SLE T cells with the caspase-3 inhibitor Z-Asp-Glu-Val-Asp-FMK reduced proteolysis of CD3 {zeta} and enhanced its expression. In addition, Z-Asp-Glu-Val-Asp-FMK treatment increased the association of CD3 {zeta} with lipid rafts and simultaneously reversed the abnormal lipid raft pre-clustering, heightened TCR-induced calcium responses and reduced the expression of FcR{gamma} -chain exclusively in SLE T cells [24]. Finally, the TCR {zeta} chain in SLE T cells shows an enhanced ubiquitination resulting in enhanced degradation [25].

In SLE T cells the decreased TCR {zeta} chain is replaced by the FCR {gamma} chain, which is usually not expressed in normal T cells [26, 27]. FCR {gamma} associates with the CD3{varepsilon} and the Syk kinase, which is regularly not expressed in T cells as well. Lack of the {zeta} chain also results in a lack of the zeta-associated protein 70 (ZAP70). Therefore, the TCR complex seems to be rewired, as FCR{gamma}-syk replaces {zeta}-Zap70. Since FCR{gamma}-syk is known to signal 100 times more efficient than {zeta}-Zap70, this might explain the overexcitability displayed by SLE T cells which is manifested with an enhanced calcium influx and tyrosine phosphorylation of cytosolic proteins, that we have observed [28] (Fig. 1).


Figure 1
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  		FIG. 1. Diagramatic summary of major SLE T-cell signalling and gene transcription aberrations. T cell receptor complex is rewired and contains FCRy instead of the TCR {zeta} chain. Lipid rafts are aggregated and along with the rewired TCR contribute to enhanced early signalling events. Constitutive adherence of CD45 to lipid rafts results in decreased lck expression. Anti-CD3/TCR autoantibodies present in the sera of patients with SLE promote CaMKIV translocation to the nucleus, which results in increased binding of CREM to the IL-2 and c-fos promoters. Increased NFAT expression results in increased activity of promoters in which NFAT does not dependent on intact AP1 activity, such as CD40L and in decreased activity of promoters in which NFAT activity is dependent on intact AP1 activity such as IL-2.

 
In addition, the distribution of signalling molecules on the surface of SLE T cells is altered, since lipid rafts do not form a uniform ring on the surface membrane of the T cell but rather they appear in patches similar to those observed on T cells following stimulation with anti-CD3 antibody. These patches form completed caps within 2 min after activation compared with cap formation in regular T cells, which takes about 10 min. The aggregated lipid rafts are metabolically active and more importantly, crosslinking of lipid rafts prior to stimulation with anti-CD3 antibody results in further enhancement of the signalling response. These data suggest that the pre-formed patches are responsible for the fast signalling response and increased Ca2+ influx in SLE T cells [24] (Fig. 1).

Another critical component of lipid raft association is lymphocyte-specific protein tyrosine kinase (PTP; lck). Lck is important for maintaining the resting state of T cells and the activation of signalling cascades. Lck phosphorylates the ITAMs of CD3 {zeta} [29–31]. ZAP70 is recruited to CD3 {zeta}, binding to dually phosphorylated ITAMs. Once recruited, ZAP70 is phosphorylated by lck or Fyn, which renders it catalytically active [30, 32], leading to phosphorylation of downstream substrates. LCK is ciritcal for phosphorylation and activation of the ERK-MAPKinase pathway and globally for T-cell effector function and cytokine production [33, 34]. The activity of lck is regulated by tyrosine phosphorylation, which is mediated by PTP CD45. CD45 maintains lck in a primed state so that the cells can readily respond to T-cell activation by dephosphorylation. In normal T cells CD45 is excluded from lipid raft domains after stimulation, while in SLE T cells it remains in the rafts over a prolonged period. Comparable the {zeta} chain enhanced ubiquitination is associated with decreased lck expression and an enhanced disease activity in SLE patients [35]. Interestingly, Inhibitors of 3-hydroxy-3-methylgluteryl CoA reductase (statins) can modify the composition of lipid rafts, resulting in alteration of T-cell signalling. In this context, atovarstatin has been claimed to restore the altered lipid raft function in SLE T cells and treatment with statins is beneficial in a SLE mouse model (NZB) [36, 37]. Interestingly, defective ERK phosphorylation has also been restored by treatment with atorvastatin [36].

Enhanced calcium influx and enhanced CaMKIV expression in SLE T cells
As mentioned above, that one of the first events after T-cell stimulation is an enhanced free cytoplasmic Ca2+ response that is enhanced in SLE T cells. However, this enhanced calcium response does not lead to an overall up-regulation of calcium dependent genes. While CD154 (CD40 ligand) is induced resulting in an enhanced B-cell stimulation, IL-2 production is decreased resulting in decreased AICD [7, 38, 39] (Fig. 1).

The enhanced Ca2+ response results in activation of several kinases like calcineurin and calmodulin kinases. Downstream targets of calcineurin are the nuclear factor of activation in T cells (NFAT), which is found enhanced in SLE T cells and binds to promoters of genes like the IL-2 and CD154 [39]. However, while NFAT mediates enhanced trancription of CD154, the enhanced binding of NFAT to the IL-2 promoter does not result in an increased IL-2 transcription. One reason for the dichotomous response is the fact that for NFAT can bind to cis sites of promoters alone or in the context to activator protein 1(AP1) bound to adjacent cis sites. The CD154 promoter defines an NFAT site but its activity does not depend on AP1 binding to an adjacent site. In contrast, the IL-2 promoter defines NFAT sites adjacent to AP1 sites. Because AP1 activity is decreased in SLE T cells [40] binding of NFAT to the IL-2 promoter does not result in increased transcriptional activity, whereas binding to the CD154 promoter results in the expected increased activity [39]. Another reason for this dichotomous phenomenon is the activation and enhanced nuclear transclocation of calcium calmoduline kinase 4 (CaMKIV) [41].

An important target of CaMKIV is the cAMP responsive element binding modulator (CREM). We have previously shown that the transcriptional repressor CREM{alpha} is expressed in increased levels in SLE T cells and binds to the –180 site of the IL-2 promoter [42] and represses its activity directly (Fig. 1). Knock-down of CREM{alpha} expression by an anti-sense CREM plasmid results in an enhanced transcriptional activity of the IL-2 promoter in SLE T cells [43, 44].

CaMKIV is increased in the nucleus of SLE T cells compared with normal T cells, while CaMKII is not. Furthermore, blockade of CaMKIV activity by transfection of an inactive form of CaMKIV in SLE T cells reduces the binding of CREM to the –180 site of the IL-2 promoter. Additionally, overexpression of additional CaMKIV in SLE T cells significantly enhances the complex formation of CREM on the IL-2 promoter and suppresses IL-2 promoter activity, while in normal T cells overexpression CaMKIV is not able to mediate this effect, pointing to the fact that CaMKIV alone is not sufficient to down-regulate the IL-2 promoter. When these normal T cells are pre-treated with SLE sera, CaMKIV is able to suppress the IL-2 promoter and those cells produce significantly less IL-2. SLE sera contain anti-CD3/TCR autoantibodies, which induce the enhanced expression and nuclear translocation of CaMKIV resulting in an enhanced CREM binding to the IL-2 promoter [41].

The finding that CaMKIV is overexpressed in SLE is of pathophysiological importance for two reasons. First, CaMKIV has a selective immune cell expression pattern, as it is expressed primarily by T cells whereas B cells and macrophages have no detectable CaMKIV expression [45], suggesting that CREM is not important in the pathophysiology of SLE in B cells and antigen-presenting cells. Second, CaMKIV is located in the cytoplasmic compartment of normal T cells, whereas in SLE T cells CaMKIV resides primarily in the nucleus [41]. Therefore, CaMKIV is aberrantly regulated in SLE T cells and may contribute to dysregulation of gene expression. There is a substantial cross-talk between CaMKIV and other kinases that activate CREM. In particular, CaMKIV is negatively regulated by protein kinase A and C (PKA and PKC) [46, 47], both of which have been reported to be less active in SLE T cells compared with normal T cells [48, 49]. Also, it has been shown that CaMKII negatively regulates the effects of CaMKIV on the activity of both CREB and ATF-1. In SLE T cells, increased nuclear levels of CaMKIV are associated with decreased levels of CaMKII. This finding is in agreement with a previous report that CaMKIV can antagonize the effect of CaMKII by inhibiting its nuclear translocation [50]. Therefore, it appears that CaMKIV exerts a dominant effect in SLE T cells that remains unopposed by PKA, PKC and CaMKII because the activity of all three kinases is decreased.

CaMKIV enzymatic activity is regulated at least at three levels: (i) the binding of Ca2+/calmodulin to CaMKIV, (ii) autophosphorylation of CaMKIV at threonine 196 and several other serine residues [51] and (iii) the phosphorylation of CaMKIV at a number of amino acids near its N-terminal by CaMK kinase (CaMKK) [52]. The complexity of the regulation of the activity of CaMKIV suggests that in both normal and SLE T cells the level of its activity at any time point must represent the effect of multiple mechanisms, and that it may range significantly.

It is interesting to note that the pathway described herein, that SLE sera induce CaMKIV translocation to the nucleus, which induces CREM binding to the –180 site of the IL-2 promoter, will affect only genes controlled by the CRE cis element and not other genes. A number of genes, such as CD40 ligand [38, 39] and IL-6, are up-regulated in SLE and are involved in providing help to B cells to produce autoantibody. Therefore, although the increased expression of CREM in SLE T cells may represent the effect of anti-TCR/CD3 antibodies present in SLE sera, other T-cell defects may be independent of the effect of serum factors [53].

With regard to the activation of CaMKIV, it should be noted that the protein phosphatase 2A (PP2A) is up-regulated in SLE T cells as well [54] and, in normal T cells it is able to deactivate CaMKIV, however, PP2A also down-regulates activity of PKA and PKC, which are able to down-regulate CaMKIV by themselves. Nevertheless, by promoting the dephosphorylation of pCREB, PP2A contributes to the decreased IL-2 expression in SLE T cells as well, which we will discuss below in more detail.

Transcriptional regulation of IL-2 and c-Fos in SLE T cells
IL-2 is a critical cytokine in the maintenance and propagation of T-cell function and it is produced at decreased levels by T cells of patients with SLE. Decreased IL-2 mRNA implies decreased transcription activity of the IL-2 promoter.

During recent years, a number of defects in the expression of transcription factors have been found in SLE T cells. These defects include changes in the expression and function of NF-{kappa}B, AP 1, CREM and CREB. We already explained partly the role of CREM in the transcriptional repression of the IL-2 promoter. The –180 site of the IL-2 promoter binds CREM as shown in shift assays [42, 55], and live cells using chromatin immunoprecipitation assays [56]. Two –180 tandem sites in front of a luciferase reporter gene are active in normal but not in SLE T cells [42]. Additionally, forced expression of a CREM plasmid led to a decreased activity of this luciferase construct as well as another construct containing the whole IL-2 promoter (–575 to +57 bp). Consequently, we were able to restore IL-2 production in SLE T cells by transfection of an antisense CREM plasmid that suppressed the expression of CREM. This was especially prominent after stimulation of the SLE T cells and shows the importance of this transcriptional repressor in SLE T cells [56]. It should be noted that in nuclear extracts of normal, unstimulated T cells, unlike SLE T cell extracts, CREB binds to the –180 site of the IL-2 promoter [43]. SLE T cells have decreased protein kinase A (PKA) activity [49] and PKA is responsible for the activation of CREB. Forced expression of PKA RI b subunit caused increased expression of IL-2 in SLE T cells [57]. Furthermore, as mentioned above, for unknown reasons SLE T cells also show an enhanced PP2A activity, which dephosphorylates CREB [54]. It is possible therefore, that defective activation of CREB may permit the expression of CREM and indirectly contribute to the suppression of the expression of IL-2.

Second, the activity of NF-{kappa}B is decreased because SLE T cells lack the p65 subunit [58], which after forming heterodimers with the p50 subunit accounts for increased expression of IL-2. SLE T cells express sufficient amounts of p50, which may homodimerize and bind to the NF-{kappa}B site of the IL-2 promoter and repress its transcriptional activity [58]. The origin of decreased p65 expression in SLE T cells is not known, but increased caspase-8 activity, which is associated with the increased spontaneous apoptotic rate of SLE cells [59], may bind to and digest the p65 chain. Interestingly, forced expression of p65 reverses the decreased production of IL-2 in SLE T cells [60]. Furthermore, a second study found an increased c-Rel mRNA and protein production [61], but the c-Rel was unable to enter the nucleus and bind to the NF-{kappa}B site to enhance transcriptional activity.

Third, the activity of AP1 is decreased in SLE T cells as a result of decreased expression of c-fos [40]. The IL-2 promoter defines a number of AP1-binding sites. AP1 builds complexes with NFAT on the IL-2 promoter [62]. Comparable with the IL-2 promoter, CREM has been shown to bind to the –57 CRE site of the c-fos promoter and blocks the c-AMP induced expression of the c-fos protooncogene [63], a prototype of the early response genes (Fig. 1). c-fos belongs to the AP 1 family of transcription factors that consists of a mixture of heterodimers and homodimers of jun (v-jun, c-jun, junB, junD) and fos (v-fos, c-fos, fosB, fra1, fra2) proteins [64]. Each protein contains a leucine zipper region that enables its dimerization with other members of the fos/jun families. The jun proteins can form homodimers among themselves while fos proteins only form heterodimers with jun. Both jun-jun and jun-fos dimers bind to the 12-O-tetradecanoate-13-acetate (TPA) responsive element (TRE) that contains the TGACTCAA motif. Soon after antigenic stimulation, jun and fos proteins are expressed and subsequently AP 1 (particularly the c-jun/c-fos dimer) binds to the IL-2 promoter. This in turn induces the expression of the IL-2 gene [40, 62].

In patients with active SLE, we were able to show decreased levels of c-fos mRNA. SLE disease activity index (SLEDAI) was compared with the levels of c-fos mRNA 1 h after stimulation of SLE T cells with PMA and ionomycine or anti-CD3 and anti-CD28. We were able to show that the post-stimulation c-fos mRNA levels are significantly decreased in active SLE patients (patients with SLEDAI of 4 or more) compared with both inactive patients (SLEDAI < 4) and controls. Furthermore, a decrease in the SLEDAI observed in two patients over time, was associated with an increase in the levels of c-fos mRNA. On the contrary, there was no effect of the type and dose of medications the patients were on, or the particular manifestations of their disease on the levels of c-fos mRNA. Consequently, we were able to up-regulate c-fos production in stimulated normal T cells by an anti-sense CREM plasmid.

The imbalance between an overactive Ca2+-mediated signalling and impaired AP 1 activation has broader consequences. As mentioned earlier, Ca2+ influx in the T cell results in the activation of NFAT. AP 1 interacts with NFAT forming complexes that up-regulate several cytokine gene promoters, including IL-2, IL-3, IL-4, granulocyte-macrophage colony stimulating factor (GM-CSF), FasL and MIP1{alpha} [40]. The up-regulation of such genes is important for the productive immune response. In the absence or decrease of AP 1 (particularly the inducible c-fos-jun dimer), the NFAT/AP 1 complexes are not formed. Thus NFAT can only up-regulate genes such as TNF{alpha} and IL-13 [39, 65] that do not require the NFAT/AP 1 complex to form. Moreover, Th2 cytokine production is skewed towards IL-10 [65, 66]. Along the same lines, T cells that have activated NFAT while lacking sufficient AP 1 do not undergo (AICD) as readily [66]. Thus, the activation of NFAT with impaired AP 1 activation results in a non-productive immune response.

In the SLE T cell paradigm, a relative imbalance between NFAT and AP 1 activation can explain the dichotomy between higher calcium responses and deficient production of IL-2 (Fig. 1). It can also help explain the in vivo and in vitro abnormality of T-cell responses to antigens [1] and the deficient AICD [67]. In the same context, Th2 cell cytokine production would be skewed towards IL-10, a cytokine that has been found to be elevated in SLE patients [68]. Interestingly, IL-10 is associated with in vivo spontaneous apoptosis of T cells [69], a mechanism that can explain the lymphopenia seen in SLE patients. It has also been proposed that this increased lymphocytic apoptosis can flood the circulation with nuclear and cytoplasmic autoantigens [1, 69] leading to perpetuation of the abnormal immune response. Additionally, enhanced expression of CD154 leads to an increased help to B cells and isotype switch and memory response in B cells. Along this line, using the calcineurin inhibitor cyclosporine A results in a repression of NFAT-mediated gene expression, restoring one half of the Ca2+-mediated signalling, while expression of CaMKIV and therefore of CREM seems to be not affected by this treatment. However, a blockade of CaMKIV and of its target CREM would be more desirable, since it would restore activation of AP1, IL-2 and also transcription of the CD3{zeta} chain.

Therapeutical options for the treatment of T-cellular abnormalities
Some of the abnormalities, which SLE T cells show are specific for the disease while others are not. As mentioned above, the down-regulation of the TCR {zeta} chain has been observed in other diseases as well like cancer and chronic infections [12]. Nevertheless, an up-regulation of the TCR {zeta} chain is desirable and could be reached by several strategies. The introduction of the caspase inhibitor IDN-6556 into clinical trials of liver transplantation is a first step, which might be a promising strategy in the long run [70]. Since the down-regulation of the TCR {zeta} chain results in an altered structure of lipid rafts [24] and a consecutive change in TCR signalling, statins, which have been able to restore lipid raft composition, and which are widely used in clinics, are promising therapeutic agents as well and placebo-controlled studies are currently in discussion [71]. Gene-targeted therapy would be another option. The use of short interfering RNA against a transcriptional repressor of the {zeta} chain like CREM could be a possible mechanism to up-regulate promoter activity of the {zeta} chain [72]. CREM is of special interest as a therapeutical target in SLE, since the nuclear translocation of CaMKIV and the up-regulation of CREM is specific for SLE T cells and has not been described in other settings [41]. Furthermore, although CREM is abundant in a lot of tissues, the missing of CREM does not result in a disease-related immunological phenotype in the CREM k.o mouse model (unpublished data). Therefore, gene-targeted therapy by specific elimination of CREM or CaMKIV via si-RNA might be possible without severe side effects. CaMKIV-inhibitors have not been used in humans so far and might be to toxic. A third option would be to block the specific actions of CREM on transcription and chromatin remodelling. CREM interacts with histone decetylases (e.g. HDAC1) to repress transcription [73] and HDAC-inhibitors like SAHA have been effective in the mrl/lpr mouse model of SLE [74]. Additionally, HDAC-inhibitors have been shown to up-regulate AP1-activity [75]. SAHA has been used in the treatment of lymphomas and of solid tumours, which has been a promising and safe therapeutical approach in this setting.

As shown earlier the imbalance between AP1 and NFAT-activation results in differential activation of a set of genes, of which one of the most prominent is CD154. NFAT is regulated via Calcineurin, therefore Calcineurin inhibitors like Cyclosporine A although used therapeutically in SLE patients, treatment of SLE T cells in vitro with calcineurin does not result necessarily in a decreased CD154 expression [76]. Direct targeting of the CD40-CD154 pathway by monoclonal antibodies against CD154 resulted in increased thromboembolic complications, because CD154 is expressed on platelets in high numbers as well [77]. Therefore, the proper therapeutic approach has to target CD154 expression directly.

Additional therapeutic options that block the T-cell–B-cell interaction like anti-CTLA4 antibodies or direct blockade of interleukins like IL-10 are promising as well but their discussion is beyond the scope of this review [78].


   Conclusions and future directions
Top
 Abstract
 Introduction
 Methods
 Conclusions and future...
References
 
Distinct abnormalities in the expression and regulation of molecules involved in the immune cell signalling and gene transcription in SLE can account for the aberrant cell function. Herein we discussed how signalling abnormalities lead to the ‘enigmatic’ phenotype of the SLE T cell, that is increased expression of CD40L which has been demonstrated to provide increased cognate help to B cells to produce autoantibodies and decreased IL-2 production, which has been shown to account for the decreased cytotoxic responses and increased rates of infection and decreased AICD that probably leads to prolonged survival of autoreactive activated T cells.

Main themes that have emerged include: (i) rewired TCR/CD3 complex with the FcR{gamma}-Syk complex operating in lieu of the CD3 {zeta} -ZAP70; (ii) aggregated, metabolically active, lipid rafts on the surface of SLE T cells; (iii) increased translocation of CaMKIV from the cytoplasm to the nucleus, which results in increased binding of CREM to the IL-2 and c-fos promoters; and (iv) decreased availability of pCREB because of increased PP2A activity in SLE T cells. The last two abnormalities determine the ratio of CREM/pCREB that binds to the IL-2 and c-fos promoters which, in concert with occupation of other cis sites, determines the transcription rates of these genes.

The studies summarized here in have accomplished two main goals: first, they have cartographed the biochemistry of the SLE T cell pointing out to differences from the normal T cells and explained how SLE T cells are different from normal T cells and second, they have identified multiple therapeutic targets that should be exploited in the treatment of human SLE. Specifically, replenishment of CD3{zeta}, inhibition of Syk kinase, silencing of CREM, silencing of PP2A, inhibition of CaMKIV and replenishment of p65 result in corrected signalling and gene transcription processes and corrected IL-2 production. If we were to assume that corrected effected T-cell function will lead to correction of autoimmune pathology, then a strong argument can be made for the treatment of SLE through the correction of SLE T-cell biochemistry.

Formula

The authors have declared no conflicts of interest.


   References
Top
 Abstract
 Introduction
 Methods
 Conclusions and future...
 References
 

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Submitted 30 January 2007; revised version accepted 3 May 2007.
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