Clinical Immunology 239 (2022) 109031

Contents lists available at ScienceDirect

Clinical Immunology
journal homepage: www.elsevier.com/locate/yclim

T cell dysregulation in SLE

Klaus Tenbrock a, *, Thomas Rauen b
a
Dept of Pediatrics, Pediatric Rheumatology, RWTH Aachen University, Aachen, Germany
b
Dept of Medicine, Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany

A R T I C L E I N F O A B S T R A C T

Keywords: T helper cells aid B cells with the production of antibodies and thus play a central role in disease development of
Lupus systemic lupus erythematosus (SLE). Numerous T helper cell abnormalities have been described in SLE patients
CD4+ T cells that contribute to disease pathophysiology and provide suitable targets for therapeutic intervention. In addition,
T follicular helper cells
T effector cell also play a less well-defined role in SLE. This review focusses on underlying molecular mechanisms
Tregs
Foxp3
of different T cell alterations in SLE.
CD8+ T cells

1. Introduction
B cells and autoantibody production are key drivers in the patho­
genesis of systemic lupus erythematosus (SLE). The most recent disease
classification system presupposes the presence of anti-nuclear anti­
bodies to establish the diagnosis of SLE [1]. Yet, B cells per se are
ineffective without appropriate support of T cells providing necessary
costimulatory signals to them. The importance of these pathways in
promoting autoantibody production have been demonstrated in genet­
ically modified lupus-prone mice or by the use of blocking antibodies
against different costimulatory molecules like inducible costimulatory
ligand (ICOS-L) and CD40 ligand [2–4]. Thus, T helper cells are of
utmost importance for SLE disease development and progression.
Numerous T cell abnormalities including alterations within cytokine
production, metabolism and epigenetic modifications have been
described that influence T helper cell function. Moreover, effector T cell
and regulatory T cell functions are also altered in SLE and will be dis­
cussed in this review. (See Fig. 1.)
1.1. The role and regulation of IL-2 (and of other cytokines)
T helper cells exert their function particularly by expression of cy­
tokines. One of the most important cytokines is interleukin (IL)-2, which
acts as T cell growth and proliferation factor. T cell dysfunction in SLE
was first described in the 80s of the last century demonstrating that SLE
T cells exhibit a decreased IL-2 production [5]. Defects in IL-2 produc­
tion and its receptor expression were linked to severe T cell dysfunction
and autoimmunity. This relates to the fact that, in addition to being a
necessary growth factor for T helper and cytotoxic T cells, IL-2 is also a
non-redundant cytokine for regulatory T cells (Tregs), which are the
gatekeepers of immune tolerance [6]. Regulatory T cells (Tregs) fail to
produce IL-2 and are thereby completely dependent on external IL-2 [7].
Decreased IL-2 production in T cells was identified in the clinical
context of enhanced viral infection rates in SLE patients suggesting an
impaired T cellular cytotoxicity [5]. This was also linked to altered
production of other cytokines including increased expression of IL-6 and
IL-10 [8]. Both contribute to non-cognate help to B cells, whereas the
decreased IL-2 expression accounts for defective production of cytotoxic
cells or defective activation-induced cell death of various T-cell subsets
including those with autoreactive specificity. First, it was unclear
whether defective IL-2 production might be taken advantage of in
therapeutic interventions. In the meantime, a number of studies have
provided proof of evidence that a low-dose IL-2 therapy is beneficial in
refractory SLE patients [9–12]. It has moreover become clear that the
mode of administration and half-life of therapeutic IL-2 affect clinical
effectiveness. This is related to the effect of IL-2 on T cells as well as on
increased selectivity for Tregs, who express a high affinity IL-2 receptor
(i.e. CD25). Enhanced half-life of IL-2 can be achieved by conjugating
the cytokine to poly(ethylene glycol). Pegylated IL-2 has a half live of 14
days and was efficient in SLE mice models as well as in cutaneous lupus
in humans and results in expansion of the peripheral Tregs compartment
[13].

* Corresponding author.
E-mail address: ktenbrock@ukaachen.de (K. Tenbrock).

https://doi.org/10.1016/j.clim.2022.109031
Received 1 February 2022; Received in revised form 2 May 2022; Accepted 2 May 2022
Available online 6 May 2022
1521-6616/© 2022 Published by Elsevier Inc.
K. Tenbrock and T. Rauen Clinical Immunology 239 (2022) 109031

1.2. Molecular basis for defective IL-2 production
The decreased expression of IL-2 is the result of different patho­
physiological defects described in SLE T cells. Beginning with signal
transduction from the cellular surface it was shown that SLE T cells
display an altered Ca2+ signaling which was related to decreased
expression of the T cell receptor (TCR) zeta chain and rewiring of the
TCR complex [14]. This is accompanied by an altered lipid raft forma­
tion on the surface of SLE T cells at the immunological synapse resulting
in enhanced signaling. In detail, the T cell receptor (TCR) zeta chain is
replaced by the FcRgamma chain which is usually an integral part of the
B cell receptor complex and not readily expressed in T cells. FcRgamma
forms a complex with tyrosine kinase Syk which in turn is capable to
signal 100 times more effectively than the TCR zeta-ZAP70 complex. It
has also been demonstrated that forced expression of the TCR zeta chain
in SLE T cells restores IL-2 production. This receptor/kinase rearrange­
ment explains the overexcitability of SLE T cells. A decreased expression
of the zeta chain in SLE T cells occurs already on the mRNA level sug­
gesting a dysregulation already at the transcriptional level. Two major
transcription factors (TF) have been identified that are involved in TCR
zeta promoter dysregulation in SLE T cells. One is the ETS1 transcription
factor E74-like factor 1 (ELF1) which regularly undergoes post­
translational modifications affecting its activity. ELF1 becomes phos­
phorylated and O-Nacetylglucosamine (O-GlcNAc) glycosylated. The
latter process is disturbed in SLE T cells and prevents ELF1 binding to the
zeta promotor and consecutive activation [15–17]. The second TF with
major effects on IL2 transcription is the cAMP responsive element
modulator (CREM). CREM is highly expressed in SLE T cells either in the
α- or ICER-isoform and accounts for numerous transcriptional, epige­
netic and metabolic abnormalities in SLE T cells. CREMα has a direct
effect by binding to the TCR zeta promotor [18]. Subsequently, it
inhibits promoter activity and thereby mRNA and protein expression. In
addition to this indirect effect on IL2 gene expression CREMα exerts
direct effects by binding to a specific binding site within the IL2 pro­
moter. This binding site is usually occupied by the transcriptional acti­
vator CREB, however decreased CREB expression results in a CREM/
CREB imbalance favoring CREM binding and thus transcriptional
repression of IL2 [19–21]. Moreover, CREM recruits the histone deace­
tylase 1 (HDAC1) to the promoter which results in the deaceylation of
histone H4, a chromatin closure and limited accessibility to the pro­
moter also by other TFs [22]. Furthermore, CREMα mediates IL2
silencing in T lymphocytes from SLE patients through a gene-wide his­
tone deacetylase 1-directed deacetylation of histone H3K18 and DNA
methyltransferase 3a-directed cytosine phosphate guanosine (CpG)-
DNA hypermethylation [23,24]. Consequently, CREM downregulation
using an anti-sense CREM plasmid restores IL-2 expression in SLE T cells
[20].
The expression of CREM itself is regulated by different promotors.
CREM isoforms consist of different splice variants containing tran­
scriptional activators and repressors depending on the presence of a
trans-activator domain that may bind to transcriptional cofactors CREB-
binding protein (CBP) or p300. CREM promotor 1 activity is regulated
by protein phosphatase (PP)2A-dependent specificity protein 1 (SP1)
phosphorylation and binding, which is found to be enhanced in SLE T
cells in combination with enhanced activating protein 1 (AP1) activity
that regulates an additional intronic promoter P2 [25,26]. PP2A
downregulation using siRNA results in enhanced binding of pCREB to
the IL-2 promoter and upregulation of IL-2. Vice versa, a transgenic
mouse that overexpresses the PP2Ac subunit in T cells displays a
heightened susceptibility to immune-mediated glomerulonephritis by
an IL-17 dependent mechanism while PP2A knock out mice show
decreased IL-17 expression and are protected in a model of experimental

Fig. 1. Schematic representation of transcription factors involved in differential cytokine expression in SLE T-cells.
AP1, Activated protein 1; CaMKII, Calmodulin Kinase II; CaMKIV, Calmodulin Kinase IV; CREB, cAMP response element binding protein; CREM, cAMP response
element binding modulator; DNMT3A, DNA methyle transferase 3A, DUSP4, Dual sepcific phosphatase 4; ELF1, ETS1 transcription factor E74-like factor 1; IL-2,
Interleukin 2; IL-17, Interleukin 17; IL-21, Interleukin 21; IRF4, Interferon regulated factor 4; mTOR, Mammalian target of rapamycin; NFAT, Nuclear factor of
activated T cells; PP2A, Protein Phosphatase 2A; STAT4, Signal transducer and activator of transcription 4; TCR, T cell receptor.

2
K. Tenbrock and T. Rauen
autoimmune encephalitis [27–30].
Moreover, CREM is regulated by The calcium modulin kinase IV
(CamKIV) which is activated in SLE T cells and can be activated in T cells
of healthy controls in the presence of SLE sera containing IgG complexes
that specifically activate the TCR in SLE. Thus, inhibition of CamKIV
prevents CREM activation and rescues IL-2 expression as well as kidney
damage [31,32]. Beyond IL-2, CREM also regulates expression of other
cytokines like IL-17 and IL-21, which both exert proinflammatory
functions and are involved in organ damage [33,34].
1.3. Regulation of IL-17 expression
IL-17-producing T cells particularly contribute to kidney pathology
in SLE. Migration of these proinflammatory cells is partially mediated by
cleaved CD95 ligand, which induces S1P receptor 3 in Th17 cells that
induces migration into the inflamed kidney and the promotion of organ
damage [35]. IL-17A and IL-17F thereby both contribute to tissue
inflammation by induction of different chemokines (e.g. MCP-1), which
recruit additional monocytes and neutrophils to the kidney. The isoform
CREMα influences transcriptional control of both IL17A and IL17F [33].
The human IL17A and IL17F genes are located in close proximity on
chromosome 6 (within a range of about 85 kb). CREMα binds to a cAMP-
responsive element, CRE (− 111/− 104), within the proximal human
IL17A promoter and increases its activity. Increased CREMα recruitment
to the IL17A and the IL17F promoters has been documented in T cells
from SLE patients [33]. This recruitment induces epigenetic remodeling
of the IL17A and F gene loci. In contrast to the effects observed at the IL2
gene locus, CREMα binding results in lower abundance of histone
deactetylase HDAC1 and DNA methyltransferase DNMT3a in the vicin­
ity to the IL17A promoter resulting in an overall increased histone H3
acetylation and reduced histone methylation as well as CpG-DNA
hypomethylation of the IL17 locus [24]. Moreover, CREMα induces
dual specificity protein phosphatase (DUSP) 4 in effector CD4+ T cells
through corecruitment of p300 [36]. DUSP4 induces IL-17A while
limiting IL-2 expression, which is also found in T cells jSLE patients. In
line with this, a T cells specific transgenic overexpression of CREMα in
mice also enhances IL-17 levels, while CREM− /− mice in which the DNA
binding domain has been disrupted and thus all CREM isoforms are
missing including ICER, IL-17 production is impaired and CREM-
deficient B6.lpr mice are protected from developing autoimmunity
[37]. While IL-17A expression is enhanced, the expression of IL17F is
downredulated by binding of CREMα to a CRE site within the IL-17F
promoter. It is suggested that an imbalance between IL-17A and IL-
17F levels and impaired assembly of IL-17A/IL-17F heterodimers,
which have reduced proinflammatory activity as compared with IL-17A
homodimers aggravates lupus pathology [38]. As already discussed
above, transcription of CREM itself is dependent on CamKIV activation
[31]. As a proof of principle, pharmacologic inhibition of CamKIV by the
inhibitor KN93 or genetic inhibition of CamKIV decreases frequency of
IL-17-producing cells and efficiently decreases lupus-like disease in
murine models [32,34]. In addition to CamKIV, Rock2, one of two Rho
kinases has an increased activity in SLE PBMCs and blockade of this
kinase reverts enhanced IL-17 as well as IL-21 expression. Moreover,
Th17 cells express TLR2, which upon activation increases histone
acetylation and reduces methylation of the IL17A and IL17F promoter
region [50]. Moreover, apart from CD4 T cells also CD4-CD8- double
negative (DN) T cells infiltrate the kidney and contribute to tissue
damage by production of IL-17 [39]. Interestingly, CREM binding to the
promoter of the transmembrane glycoprotein CD8 contributes to the
generation of pathogenic DN T cells. With that respect, we were able to
show that CREMα overexpression in a Fas (CD95)− /− lupus mouse model
strongly accelerates lymphadenopathy and splenomegaly, which was
related to a massive expansion of DN T cells [40].
Recent papers suggest that gut microbiota dysbiosis is involved in
SLE pathogenesis [41–44]. It is currently unclear whether this is caus­
ative or merely an epiphenomenon. It has been suggested that the
3
Clinical Immunology 239 (2022) 109031
molecular mimicry between bacterial epitopes and autoantigens ac­
counts for abnormal CD4+ T cell differentiation including enhanced
expression of IL-17. It was shown in lupus-prone mice that supplemen­
tation with Lactobacillus acidophilus reduced IL-17 and DN T cell
expression during treatment with tacrolimus while it enhanced expres­
sion of IL-10 [45]. It is tempting to speculate that metabolites provided
by altered gut microbiota influence T cell function and it was shown that
glycolysis is enhanced in Th17 cells. Again, CREM/ICER regulate
expression of pyruvate dehydrogenase (PDH), which in its active
dephosphorylated form advances energy supply by using oxidative
phosphorylation. CREM/ICER thereby bind and suppress the Pdp2 pro­
moter, which regulates expression of PDH [46] resulting in an enhanced
glycolysis and IL-17 production. Moreover, another metabolic alteration
is enhanced glutaminolysis. Th17 induction depends on glutaminolysis
and upregulation of glutaminase 1 (Gls1) which is one of the key en­
zymes to mediate the metabolic breakdown of glutamine. The Gls1
promoter contains a CRE site and its function depends on CREM/ICER
binding. CREM-deficient murine T cells show reduced activity of
oxidative phosphorylation rates in the presence of glutamine and
reduced Gls1 expression [46]. Vice versa, glutaminase 1 inhibition
improved autoimmune pathology in MRL.lpr mice, and suppressed Th17
differentiation of T cells from patients with SLE but not in those from
healthy donors [47].
Additional metabolic alterations have been unraveled in another
murine lupus model demonstrating abundance of the metabolite tryp­
tophane which is produced by altered gut microbiota [43]. Pathophy­
siologically, it is suggested that the tryptophane metabolite kynurenine
binds AhR and activates mechanistic target of rapamycin (mTOR) C1 in
human T cells, which provides a rationale for treatment with the mTOR
inhibitors rapamycine and sirolimus. This is particularly interesting
since mTOR regulates cellular growth and energy utilization. CD4+ T
cells from SLE patients display enhanced mTOR activation [48], which
enhances glycolysis and fatty acid synthesis, 2 major metabolic path­
ways that favor Th17 differentiation [49,50] resulting in a Th17/Treg
imbalance in SLE patients.
1.4. Regulation of IL-21 expression
IL-21 is a pleiotropic cytokine primarily expressed by T follicular
helper cells (TfH cells). TfH cells are located in the germinal centers and
provide IL-21-dependent help for B cell differentiation in order to pro­
duce (auto)antibodies. This cytokine is indeed of utmost importance for
the generation of autoreactive B cells as demonstrated in experiments in
which the IL-21R signaling pathway was blocked in mice by genetic
modification [51] or the use of antibodies. In addition to IL-21, TfH cells
also provide contact-dependent T cell help using molecules like CD40L-
CD40 [52], inducible T cell co-stimulator (ICOS)- ICOSL signaling and
signaling lymphocyte activation molecule-associated protein (SAP) [2].
The first one has been evaluated in clinical trials, yet not proven to be
promising due to enhanced thromboembolic complications, most likely
since CD40 is also expressed on thrombocytes [4]. However, mice
models demonstrated decreased autoantibody production after use of
blocking antibodies against ICOSL [53] and CD40L [52].
With regard to IL-21, the downregulation of the CD3 zeta chain in­
duces an altered lipid raft formation at the T cellular receptor complex.
This affects signal transduction of the immunological synapse in T cells,
which results in a lower excitation threshold and enhanced Ca2+
signaling [14]. Mice with a transgenic overexpression of CREMα spe­
cifically in T cells display decreased IL-2 expression, but strikingly, and
in analogy to human SLE also enhanced Ca2+ signaling in T cells. Ca2+ is
central for IL-21 transcription, since it activates NFAT, which is the most
important transcription factor for activation of the IL-21 promoter [54].
In addition, a CRE-halfside was identified within the IL21 promoter,
which is crucial for the whole promoter activity and is able to bind
CREMα. Interestingly, in analogy to the murine and human IL17 pro­
moter CREMα displays activator function for IL-21. Autoimmune-prone
K. Tenbrock and T. Rauen
Fas (CD95)− /− mice with a transgenic overexpression of CREM in T cells
show enhanced anti-dsDNA autoantibody and enhanced total IgG pro­
duction [55,56] which could be related to this fact.
In addition to CREM, other factors influence IL-21 expression in TfH
cells in SLE as well including signal transducer and activator of tran­
scription factor STAT4. Levels of pSTAT4 expression in circulating Tfh-
like cells from SLE patients were significantly increased as compared to
healthy controls [57]. Maintenance of Tfh cell cytokine synthesis
including IL-21 was driven by type I IFNs, which activate pSTAT4
signaling. In addition to follicular T helper cells, which are characterized
by CXCR5 expression and provide B cell help in germinal centers, PD-
1hiCXCR5-CD4+ T cells from SLE patients are T peripheral helper (Tph)
cells, a CXCR5- T cell population that also stimulates B cell responses via
IL-21 in the extrafollicular department. This population is critically
dependent on the transcription factor c-MAF and a deletion of MAF
inhibited both, IL21 and IL10 mRNA expression in human CD4+ T cells
and reduced secretion of IL-21 [58].
Beyond Tfh cells, there is evidence of extrafollicular germinal center
existence in patients with SLE. B cells and plasma cells within these
extrafollicular germinal centers depend on the help of extrafollicular
CD4+ T cells. As in TfH cells, extrafollicular CD4+ T cells express Bcl-6
as a master transcriptional regulator and their antibody response de­
pends on IL-21. While these extrafollicularly enriched circulating CD4+
T cells express the lymph node homing receptor CXCR5+ and have been
documented in lupus nephritic kidneys in close contact with B cells,
there is evidence for a CXCR5-negative CD4+ T helper cell subset named
peripheral (TpH) cells. These cells have also been identified in other
rheumatic diseases including juvenile idiopathic arthritis [59]. Since
these cells also produce IL-21 and provide B cell help [58,60] it is now
quite accepted that there are different populations of IL-21-producing T
helper cells that provide B cell help in different niches including the
blood and which may transmigrate to inflamed tissue.
It has been recently published that function and expression of TFH
cells is metabolically controlled by phosphatidylethanolamine [61].
Interestingly, lipid profiles of SLE patients are different from patients
with rheumatoid arthritis (RA) and healthy controls. UPLC-MS/MS-
based plasma lipidomics reveal strikingly enhanced levels of phospha­
tidylethanolamine in accordance to disease activity levels as measured
by SLEDAI [62]. Moreover, anti-phosphatidylethanolamine antibodies
play a key role in the diagnosis of the antiphospholipid syndrome. In
addition, mechanistic target of rapamycin (mTOR) is enhanced in SLE
CD4+ T cells and IL-21 itself stimulates mTORC1 and mTORC2. IL-21
thereby impairs autophagy, differentiation, and function of Treg cells
[63].
1.5. Regulation of IL-10 expression
IL-10 is regarded as an antiinflammatory cytokine, which is one of
the key regulatory molecules mainly provided by Tregs, but also by type
1 regulatory cells (Tr1), which are primarily characterized by IL-10
production. The switch towards a Tr1 phenotype can be mediated by
T cell activation via complement regulator CD46, again a receptor
dependent on IL-2 and expression of CREM/ICER [64]. IL-10 inhibits
upregulation of MHCII on antigen-presenting cells and prevents the
production of cytokines by inhibition of glycolysis and promotion of
oxidative phosphorylation. Furthermore, IL-10 suppresses mammalian
target of rapamycin (mTOR) activity in antigen-presenting cells [65].
Despite its tolerogenic effects on T cells, IL-10 is a well-known B cell
growth and differentiation factor. It enhances survival, proliferation,
isotype switching, and differentiation of human B cells to plasma cells
and has thus been associated with SLE.
Increased levels of IL-10 were found in sera and tissues from SLE
patients [59,66] and have been linked to reduced DNA methylation of
the IL10 gene [67]. Furthermore, blockade of IL-10 relieved some of the
cellular features in vitro [68]. We were able to demonstrate that IL-10
production is also regulated at the extracellular level via the YB-1/
4
Clinical Immunology 239 (2022) 109031
Notch-3 axis in SLE patients [69]. Y-box binding protein-1 (YB-1) is a
pleiotropic protein that acts as transcriptional or translational regulator,
but may also be actively secreted by inflammatory cells such as activated
monocytes [70]. In sera from active SLE patients and kidneys with lupus
nephritis, we found increased levels of YB-1 with a specific post­
translational modification, i.e. guanidinylated YB-1 (YB-1-G). Notably,
YB-1-G can bind to the extracellular domains of transmembrane Notch-3
receptors and thereby activate its intracellular signaling processes that
eventually result in enhanced IL-10 production. Along these lines, lupus-
prone mice with constitutional Notch-3 depletion showed an aggravated
lupus phenotype with significantly increased mortality, enlarged
lymphoid organs and fewer Tregs, however reduced IL-10 amounts and
aggravated nephritis [69].
Specific blockade of IL-10 prevents B cell responses in a murine
model of SLE [8]. In a recent publication extrafollicular, IL-10-
producing CCR6+ helper T cells were identified which are found high­
ly abundant in lymph nodes of SLE patients and colocalize with B cells at
the margins of follicles. These cells can also be identified in lymph nodes
and circulation of autoimmune prone mice [71]. While it is clear that IL-
10 exerts anti-inflammatory properties, it is also an important cytokine
for the B cell response against e.g. plasmodium infections [72] and
interestingly, patients with Plasmodium falciparum malaria display
increased levels of circulating anti-DNA antibodies and immune com­
plexes containing parasite DNA [73].
1.6. Tregs in SLE
Regulatory T cells (Tregs) are gatekeepers of immunological toler­
ance, characterized by the master transcriptional regulator Foxp3 [74]
and have been extensively studied with respect to numbers and partially
function in human SLE. However, the results are mixed, which is related
to different markers used for staining and isolation of these cells. Foxp3
can naturally not be used for sorting and functional analysis, since it is
an intracellular marker. Therefore, some studies report reduced
numbers or impaired function of circulating Treg cells in SLE patients
[75,76], while other groups observed no abnormalities [77,78]. Indeed,
some studies report increased levels of Treg cells in SLE as compared to
those in healthy controls [79,80] or a resistance of lupus effector T cells
to Treg suppression instead of functional defects of SLE Treg cells [81].
The expression of Foxp3 and thus the functional capacities of Tregs
critically dependent on the methylation status within the so called
TSDR. There is currently no evidence that this methylation status is
impaired in SLE Tregs suggesting that there is no primary defect in Tregs
in SLE. Nevertheless, different cytokines within the inflamed local
milieu might influence Treg function. As mentioned above, IL-21 affects
mTOR activity and mTOR is one of the important energy sensors in
living cells including Tregs [63].
One critical point with regard to Treg expansion is indeed the
external supplementation with IL-2, since Tregs are not able to produce
IL-2 by themselves. This again suggest a rather secondary effect in Tregs
exemplified by the fact that low dose IL-2 treatment enhances expression
of Tregs in human SLE patients as well as in murine lupus models.
1.7. CD8 T cells in SLE
CD8 effector T cells are important for the clearance of virus-infected
cells through production of perforins and granzymes. Several functional
deficiencies in CD8 T cells obtained from SLE patients have been noted
like downregulation of SLAM4 [82], which might correlate with poor
control of Epstein-Barr virus infection [83,84] and predisposition to
infection. With that respect, low dose IL-2 therapy enhances viral
clearance and control of viral infections in SLE patients as well as in
lupus mouse models infected with influenza A [85], however also ex­
pands IL-13- and interferon-γ-producing CD8 + T cells via the STAT6-
GATA-3 axis in SLE patients [86]. These cells can be pathogenic under
certain circumstances. This is particularly important since it has not
K. Tenbrock and T. Rauen
been noticed within the local inflamed tissue. Interestingly some of these
CD8 effector cells show a metabolically and functionally exhausted
phenotype [87] while others are functionally intact and build different
clusters of CD8 effector cells, e.g. in affected kidneys in cooperation with
other cell types like NK cells. Thus, there are discrepancies between the
functional effector properties in tissue resident CD8 cells and blood
derived CD8 cells, which are not easily explained and which could be
affected by future treatment regimens.
1.8. Double Negative T cells in SLE
CD4-CD8- double negative (DN) T cells are expanded in SL, which
most probably arise from CD8+ T cells. DN T cells are pathogenic, since
they produce IL-17, infiltrate the kidney and induce tissue damage [39].
It was shown that CREMα trans-represses CD8 expression. CREMα or­
chestrates epigenetic remodeling of the CD8 cluster through the
recruitment of DNMT 3a and histone methyltransferase G9a [88–90].
CD8 T cells lose CD8 expression and become DN only when cognate Ag is
sensed as self, this means that infectious antigens are unable to induce
DN T cells. In addition, a loss of marginal zone macrophages (MZM) is
described in patients with SLE and induces expression of DN T cells
[90–92]. The loss of these macrophages impairs the tolerogenic clear­
ance of apoptotic cells. MZM defects generate an inflammatory milieu,
in which elevated IL-23 along with reduced TGFβ facilitate self-reactive
DN T-cell activation, expansion, and survival, which are generated from
self-reactive CD8+ T cells. Importantly, the therapeutic effects of rapa­
mycin in SLE were associated with the reduction of IL-17-producing DN
T cells in a recently published trial [93].
1.9. T cell signatures as potential biomarkers
With regard to personalized medicine approaches it becomes
increasingly important to stratify patients into categories related to
organ involvement, disease manifestations and biomarkers that define
response to therapy. The so called interferon signature, which compro­
mises a RNA expression analysis of 5–15 genes is one of the biomarkers
used but there are conflicting results regarding their predictive values
with respect to disease activity, prednisolone usage and therapeutic
response [94–96]. This situation is even more complex with regard to T
cell specific markers. Numerous markers on T cells including DNA
methylations on promoters and miRNA expression have been exploited
in SLE cohorts and correlated with SLEDAI scores with mixed results
[97–100]. This may reflect the complexity of disease and also the
different involvement of T cells in different organ manifestations.
Nevertheless, it is highly probable that future therapeutic strategies
include biomarker analysis prior to start of medication.
2. Conclusions
T cells are of utmost importance in the pathogenesis of SLE and
already serve as drug targets. IL-2 is the example par excellence in which
a clinical observation made it to the bench and back to the patient and
thus resulted in a therapeutic intervention that is about to reach
approval by regulatory authorities. Some of the herein described T cell
abnormalities might also be suitable targets for therapeutic in­
terventions in the future. With respect to our patients, they are urgently
needed.
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