Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2017 Dec 1.
Published in final edited form as: Curr Opin Immunol. 2016 Sep 13;43:32–38. doi: 10.1016/j.coi.2016.09.001

T cells in Systemic Lupus Erythematosus

Abel Suárez-Fueyo 1, Sean J Bradley 1, George C Tsokos 1
PMCID: PMC5125867  NIHMSID: NIHMS815243  PMID: 27636649

Abstract

Systemic Lupus Erythematosus is an autoimmune disorder caused by a complex combination of genetic, epigenetic and environmental factors. Different polymorphisms and epigenetic modifications lead to altered gene expression and function of several molecules which lead to abnormal T cell responses. Metabolic and functional alterations result in peripheral tolerance failures and biased differentiation of T cells into pro-inflammatory and B cell-helper phenotypes as well as the accumulation of disease-promoting memory T cells. Understanding these T cell alterations and their origins is necessary to develop more accurate patient classification systems and to discover new therapeutic targets.

Graphical Abstract

graphic file with name nihms815243f3.jpg

Introduction

SLE is a complex autoimmune disease characterized by defects in cellular apoptotic debris clearance, an interferon (IFN) expression signature in peripheral lymphocytes, and the breakdown of peripheral tolerance mechanisms resulting in the generation of autoantibodies and damage of tissues and organs, including the kidney (reviewed in [1]). T cells play a major role in SLE pathogenesis, amplifying inflammation by secretion of pro-inflammatory cytokines, helping B cells to generate autoantibodies, and maintaining the disease through the accumulation of autoreactive memory T cells. Many aberrations in T cell expression and function have been described as related to abnormal T cell activation in SLE patients (reviewed in [2]) which leads to reduced TCR activation threshold and reduced peripheral tolerance.

During the last few years, special interest has been focused on the role of T cell subsets in SLE pathology, the molecular pathways involved in their aberrant differentiation and their varied metabolic needs. In this review we discuss the role of T cells in SLE as well as current knowledge of associated molecular alterations. Clearer understanding of these aberrations will lead to the development of new and more specific SLE treatments.

SLE T cells show widespread inflammatory gene expression

In addition to the IFN gene signature, T cell transcriptome data highlights induction of pathways related to mitochondria, glycolysis and nucleotide metabolism, as well as genes induced in patients with anti-dsDNA antibodies and nephritis. T cell gene expression can also be used to stratify patients into subtypes which may facilitate precision medicine approaches [3]. Many of the induced genes are present in other peripheral blood cells ([4]). While some of the altered genes and pathways are already validated in the literature, such as increased mitochondrial oxidative phosphorylation and glycolysis [5], further validation and functional analysis should lead to a better understanding of the disease and development of new and more precise (personalized) therapeutic treatments.

T cells, a complex group of different cells with specific functions that are altered in SLE

Recent advances in detection methods reveal immense complexity in peripheral blood T cell subpopulations [6], including different effector, memory and regulatory subtypes.

While the immune system relies on complex interactions of different cells, these can be broadly classified as pro- or anti-inflammatory. T cells can drive immunosuppression or inflammation and antibody production, based on the proportion of different T cell subpopulations and their signaling function. The prevalence of T cell subtypes can vary widely but SLE patients show consistent differences in the ratios of some T cell subsets as well as abnormalities in their function (Fig. 1). The role of these cells in SLE pathogenesis has been studied during the last years and are commented on below.

Figure 1. Dysregulation of T cell function and subpopulation ratios drive SLE pathogenesis.

Figure 1

Open in a new tab

Reduced T cell regulatory and cytotoxic functions lead to increased pro-inflammatory and follicular helper T cell subpopulations that infiltrate tissues contributing to inflammation and auto-antibody production (red line indicates up-regulated and the blue line for down-regulated).

Reduced cytotoxicity in SLE CD8 T cells

CD8 T cells control infection, malignancy and autoreactive immunity by release of cytotoxic proteins such as perforin and granzymes. CD8 T cells in SLE have dampened cytotoxic function that can lead to increased risk of infection, which may also trigger autoimmunity [7]. Two recent studies showed defective CD8 responses to viral antigens, and proposed either a reduction in effector memory CD8 T cells positive for Signaling lymphocytic activation molecule family member 4 (SLAMF4) which is related to conversion of CD8 into double negative (DN) T cells [8], or increased expression of the inhibitory programmed death receptor 1 (PD-1) [9], an inhibitory receptor that is expressed under continuous TCR stimulation without co-stimulatory molecules. Induction of exhaustion has been proposed as therapy for autoimmune disease, as an exhaustion transcriptome profile marks patients with better clinical outcomes [10]. Such therapies may increase susceptibility to infections, the highest cause of death in SLE, so careful consideration will be required [1]. In addition, PD-1 plays a role in the generation of DN T cells from autoreactive T cells [11], which plays a pathogenic role in SLE. The conversion of CD8 T cells into double-negative T cells, as well as PD-1 expression, could explain the loss of cytotoxicity against viruses in SLE CD8 T cells.

Double-Negative T cells in SLE: from suppressive to pro-inflammatory

Double-Negative (DN) T cells, defined as TCRαβ+CD4−CD8−, can result from inactivation or exhaustion of autoreactive, or continuously stimulated CD8 T cells, such as are found in chronic infection [12,13]. Under normal conditions an immunosuppressive role has been attributed to these cells, both in mouse and human, through antigen-competition and T cell killing by Fas-FasL or perforin and granzyme secretion [14,15]. However, in SLE patients these cells are related to pathogenesis and kidney disease where they accumulate and produce the pro-inflammatory cytokine IL-17 [16] (Fig. 1).

Increased mitochondrial mass and mitochondrial potential dysfunction have been described in DN T cells from SLE patients, leading to mTOR activation and expansion of DN T cells producing IL-17 [17]. Increased expression and activation of CREMα in SLE T cells was also shown to contribute to generation of DN T cells [18] and IL-17 production [19]. Additionally, the immunosuppressive function of DN T cells is affected by PI3K/AKT/mTOR activity [20], which is increased in SLE T and B cells [21](Fig. 2).

Figure 2. Aberrant signaling in SLE T cells leads to impaired regulatory function and differentiation into TH17 and TFH cells.

Figure 2

Open in a new tab

The different pathway colors are arbitrarily assigned to facilitate visualization.

CD4 T helper cells, supporting inflammation and autoantibody production in SLE

CD4+ helper T cells make major contributions to antibody production and tissue inflammation, and are readily linked to development of SLE and Lupus nephritis. Aberrant expression of different molecules and signaling leads to increased TCR stimulation and circumvention of peripheral tolerance mechanisms (Fig. 2 and [2]). In addition, increased accumulation of effector/memory T cells has been described in these patients, which is thought to result from activation of PI3K/AKT/mTOR transduction, conferring resistance to activation-induced cell death [21]. In addition to effector/memory T cell accumulation, there is a skewing toward T Helper (TH)17 cell production with down-regulation of the TH1 and regulatory T cell (Treg) cytokines, IFNγ and TGFβ, and the up-regulation of IL-6 and IL-17, TH17 cytokines [22]. Additionally, an increase in a subpopulation of extra-follicular T helper cells has been described in peripheral blood from SLE patients, helping to explain increased B cell activation and autoantibody production [23–26].

Increased numbers of T helper 17 cells promote kidney disease and autoantibody production

TH17 cells and the cytokine IL-17 are related to SLE disease and especially with lupus nephritis (Fig. 1). IL-17 is a potent pro-inflammatory cytokine, the levels of which correlate with the development of lupus-like nephritis in several mouse models. In addition, the proportion of TH17 cells and the amount of IL-17 in serum are increased in SLE patients, especially in those with kidney disease (Fig. 1 and reviewed in [27]).

There are several molecular aberrations in SLE patients that lead to an increase in IL-17 production and TH-17 kidney infiltration (Fig. 2). Stimulation of SLE T cells through TLR2, a molecule increased in SLE CD4 T cells upon activation of the Syk pathway [28], leads to chromatin opening at the promoters of IL-17A and IL-17F through increased histone acetylation and reduced DNA methylation [29], and activates NF-κB [30]. The protein phosphatase (PP) 2A is increased in SLE T cells; it also controls the IL-17 promoter, inducing hypomethylation by suppressing the DNA methyltransferase 1 pathway, promoting acetylation of histone 3 [31,32], and facilitating the binding of IRF4 which is activated by Rho-associated protein kinase (ROCK)[33]. Activation of CaMKIV leads to CREMα and RORγ binding to the IL-17 promoter and the transcription of this cytokine via activation of the PI3K/AKT/mTOR pathway [19]. In addition, CAMKIV has been linked to expression of CCR6, which facilitates recruitment of TH17 cells to the kidney[34]. AKT inhibition reduces in vitro TH17 migration in response to CCL-20 [35], probably as a consequence of altered signaling through ROCK, which is more active in SLE T cells and is involved in CCR6 and CD44 signaling [36]. IL-17 also contributes to the loss of B cell tolerance in an autoimmune mouse [37], adding a new role to DN and TH17 cell function in SLE pathogenesis.

Extrafollicular T cells help B cells to produce autoantibodies in SLE

SLE is characterized by production of high affinity autoantibodies against nuclear antigens, of which anti-dsDNA has been most correlated with disease activity[1]. The IgG isotype and somatic hypermutation in these autoantibodies indicates that that B cells are activated in a T-cell dependent-manner [38]. B cell activation depends on interaction with T follicular helper (TFH) cells, a subtype of CD4 T cells positive for CXCR5, PD-1, ICOS and CD40L. In addition these cells express high levels of IL-21 and IL-10 which costimulate B cells to differentiate into memory B cells and plasmablasts [39].

Several groups have shown significant increases in T cells with a follicular helper-like phenotype in peripheral blood from SLE patients [23–26]. These cells are characterized by CXCR5 expression. These cells also express ICOS, PD-1, CD57, BTLA, and produce IL-21, confirming the TFH-like nature of these cells [24,26].

The number of extrafollicular T helper cells correlates with antibody titers, especially anti-DNA and plasmablast B cells in peripheral blood from SLE patients. In addition these cells have been found in lymphoid aggregates and ectopic germinal centers in lupus nephritis lesions expressing ICOS, PD-1, Bcl-6 and IL-21 [40]. Induction of B cell differentiation into plasmablasts depends on CD40L but not on ICOS expression in TFH [25]. However, ICOS signaling, as well as OX40, through p110δ, are necessary for TFH differentiation [41,42].

TFH differentiation requires Bcl-6, a transcription factor regulated by Signal transducer and activator of transcription (STAT)3, following IL-6 and IL-21 stimulation which can be inhibited by IL-2 through STAT5 activation [43–45]. The combination of signals that are necessary needs further investigation since contradictory data exists on the role of the PI3K/AKT/mTOR pathway [46,47]. Down-regulation of IL-2, increased levels of IL-6 and IL-21 in serum from SLE patients [48], and higher expression of ICOS and OX40 on SLE T cells can lead to increased differentiation of TFH over TH1 cells and support autoantibody production both in classical and ectopic germinal centers (Fig. 1 and 2).

γδT cells

γδT are a minor population of T cells related to SLE pathology, both in humans and in mouse models, through their antigen-presenting function, pro-inflammatory cytokine secretion, interaction with Treg, and their promotion of antibody production by providing B cell help even in absence of antigen (reviewed in [49])

Recently, a report showed that one subtype of the γδT cell population, Vδ2, is reduced in peripheral blood but accumulates in kidneys from SLE patients. These cells display an activated phenotype with expression of different chemokine receptors, CD40L and IL-21, indicating a possible role in B cell stimulation [50] and a role for γδT cells in lupus nephritis.

Impaired Regulatory T cells in SLE

T regulatory cells (Treg) include several subsets of T cells playing a critical role in the control of the immune system. While the classical Treg are a subset of the TCRαβ CD4+ cells, TCRαβ CD8+ and γδT cells have also been described to have regulatory activity (reviewed in [51]). While it is well accepted that there is a dysregulation in immune response control by Treg in SLE patients, the cause remains unclear.

CD4+ T Regulatory Cells

CD4 Treg cells are marked by high expression of IL-2 receptor alpha (CD25) and transcription factor Forkhead box P3 (FoxP3), coupled with low levels of IL-7 receptor alpha (CD127). Because different markers are used in the literature, the number of Treg in the peripheral blood of SLE patients, as well as their function are conflicting (reviewed in [52]). A dysregulation between effector and Treg balance is evident and this may be a result of several molecular aberrations. Activation of the PI3K/AKT/mTOR [21,53] and CaMKIV [54] pathways in SLE T cells accounts for differentiation into TH17 or DN negative T cells and reduced differentiation into Treg by a mechanism that implicates IL-2 shortage [19,53]. This is supported by recent studies in lupus-prone mice where inhibition of CaMKIV, which restores IL-2 production [55], or increased IL-2 production by gene-therapy [56], enhanced Treg levels resulting in diminished organ inflammation. Even more compelling, clinical trials showed that low doses of IL-2 reduced disease activity, coupled with expansion of the Treg cells and decreased levels of anti-dsDNA antibodies in SLE patients [57,58]. Rapamycin treatment of SLE T cells in vitro leads to expansion of Treg with sustained suppressive activity [53,59], and a clinical trial using N-acetylcysteine, an inhibitor of mTOR, also showed reduced disease activity and increased Treg populations [60].

CD8+ T Regulatory Cells

CD8 T regulatory cells (CD8 Treg) also express FOXP3, high levels of CD25 and low levels of CD127, but also several membrane molecules such as CTLA-4, GITR, etc., (reviewed in [61]). CD8 Treg inhibit immune responses through mechanisms such as cytokine release or direct contact with target cells. Importantly, it has been shown that CD8 Treg control adaptive immune responses through inhibition of follicular helper T cells mediated by Qa-1, the ortholog of human HLA-E [62]. CD8+ Treg from patients with SLE show defective suppression of effector T cell proliferation [63,64]; however, more studies are required to further characterize specific functions of these cells in SLE patients. Interestingly, antibodies against HLA-E have been described in SLE serum [65], raising the possibility that these antibodies are interfering with CD8 Treg activity.

γδ Regulatory T Cells

A subpopulation of γδT cells expressing FoxP3, high levels of CD25 and CD27, and low levels of CD45RA, also can suppress autologous T cell proliferation. SLE patients showed significantly fewer circulating γδTreg cells in the periphery [66], but more studies are needed in order to define the function of these cells.

Conclusions

T cells play an important role driving and maintaining SLE disease. Decreased cytotoxicity of CD8 T cells has a role in increased risk of infection. Up-regulation and accumulation of T follicular helper, γδT cells, TH17 and DN T cells, and down-regulation of suppressive function of the different regulatory subsets, drive and maintain the synthesis of autoantibodies and have a strong influence over kidney pathology in SLE patients (Fig. 1). At the molecular level, the pathways and molecular aberrations that lead to activation of CaMKIV, ROCK, STAT3 and PI3K/AKT/mTOR are important for differentiation of TH17 and TFH and for suppression of differentiation and function of Treg. These molecules seem to be promising therapeutic targets with clinical trials underway (Fig. 2). Careful consideration of T cell subsets, coupled with patient stratification by immunophenotyping and expression analysis, holds great promise for the development of new and more personalized therapies in SLE.

Highlights.

  • -

    T cell transcriptomes can stratify patients.

  • -

    TH17, Double Negative and γδT cells contribute to lupus nephritis.

  • -

    T cell support autoantibody production in lymphoid and non-lymphoid organs in SLE.

  • -

    Aberrant activation of several pathways drives T cell malfunction in SLE.

  • -

    CaMKIV, ROCK, STAT3 AND PI3K/AKT/mTOR represent therapeutic targets.

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Contributor Information

Abel Suárez-Fueyo, Email: afueyo@bidmc.harvard.edu.

Sean J. Bradley, Email: sjbradle@bidmc.harvard.edu.

George C. Tsokos, Email: gtsokos@bidmc.harvard.edu.

Bibliography

  • 1.Tsokos GC. Systemic Lupus Erythematosus. N. Engl. J. Med. 2011;365:2110–2121. doi: 10.1056/NEJMra1100359. [DOI] [PubMed] [Google Scholar]
  • 2.Moulton VR, Tsokos GC. T cell signaling abnormalities contribute to aberrant immune cell function and autoimmunity. J. Clin. Invest. 2015;125:2220–2227. doi: 10.1172/JCI78087. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3. Bradley SJ, Suarez-Fueyo A, Moss DR, Kyttaris VC, Tsokos GC. T Cell Transcriptomes Describe Patient Subtypes in Systemic Lupus Erythematosus. PLOS ONE. 2015;10:e0141171. doi: 10.1371/journal.pone.0141171. * T cell trancriptome analysis was used as an expression screen to identify symptom-related and patient stratification biomarkers.
  • 4. Banchereau R, Hong S, Cantarel B, Baldwin N, Baisch J, Edens M, Cepika A-M, Acs P, Turner J, Anguiano E, et al. Personalized Immunomonitoring Uncovers Molecular Networks that Stratify Lupus Patients. Cell. 2016;165:551–565. doi: 10.1016/j.cell.2016.03.008. *Microarray analysis over years in pediatric SLE patients was used to identify patient subpopulations on the basis of gene expression in whole blood samples.
  • 5.Yin Y, Choi S-C, Xu Z, Perry DJ, Seay H, Croker BP, Sobel ES, Brusko TM, Morel L. Normalization of CD4+ T cell metabolism reverses lupus. Sci. Transl. Med. 2015;7:274ra18–274ra18. doi: 10.1126/scitranslmed.aaa0835. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Wong MT, Chen J, Narayanan S, Lin W, Anicete R, Kiaang HTK, De Lafaille MAC, Poidinger M, Newell EW. Mapping the Diversity of Follicular Helper T Cells in Human Blood and Tonsils Using High-Dimensional Mass Cytometry Analysis. Cell Rep. 2015;11:1822–1833. doi: 10.1016/j.celrep.2015.05.022. [DOI] [PubMed] [Google Scholar]
  • 7.Gravano DM, Hoyer KK. Promotion and prevention of autoimmune disease by CD8+ T cells. J. Autoimmun. 2013;45:68–79. doi: 10.1016/j.jaut.2013.06.004. [DOI] [PubMed] [Google Scholar]
  • 8.Kis-Toth K, Comte D, Karampetsou MP, Kyttaris VC, Kannan L, Terhorst C, Tsokos GC. Selective Loss of Signaling Lymphocytic Activation Molecule Family Member 4–Positive CD8+ T Cells Contributes to the Decreased Cytotoxic Cell Activity in Systemic Lupus Erythematosus. Arthritis Rheumatol. 2016;68:164–173. doi: 10.1002/art.39410. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Larsen M, Sauce D, Deback C, Arnaud L, Mathian A, Miyara M, Boutolleau D, Parizot C, Dorgham K, Papagno L, et al. Exhausted cytotoxic control of Epstein-Barr virus in human lupus. PLoS Pathog. 2011;7:e1002328. doi: 10.1371/journal.ppat.1002328. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.McKinney EF, Lee JC, Jayne DRW, Lyons PA, Smith KGC. T-cell exhaustion, co-stimulation and clinical outcome in autoimmunity and infection. Nature. 2015;523:612–616. doi: 10.1038/nature14468. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Rodríguez-Rodríguez N, Apostolidis SA, Penaloza-MacMaster P, Martín Villa JM, Barouch DH, Tsokos GC, Crispín JC. Programmed cell death 1 and Helios distinguish TCR-αβ+ double-negative (CD4−CD8−) T cells that derive from self-reactive CD8 T cells. J. Immunol. Baltim. Md 1950. 2015;194:4207–4214. doi: 10.4049/jimmunol.1402775. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Thomson CW, Lee BP-L, Zhang L. Double-negative regulatory T cells: non-conventional regulators. Immunol. Res. 2006;35:163–178. doi: 10.1385/IR:35:1:163. [DOI] [PubMed] [Google Scholar]
  • 13.Rodríguez-Rodríguez N, Apostolidis SA, Fitzgerald L, Meehan BS, Corbett AJ, Martín-Villa JM, McCluskey J, Tsokos GC, Crispín JC. Pro-inflammatory self-reactive T cells are found within murine TCR-αβ(+) CD4(−) CD8(−) PD-1(+) cells. Eur. J. Immunol. 2016 doi: 10.1002/eji.201546056. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Voelkl S, Gary R, Mackensen A. Characterization of the immunoregulatory function of human TCR-αβ+ CD4− CD8− double-negative T cells. Eur. J. Immunol. 2011;41:739–748. doi: 10.1002/eji.201040982. [DOI] [PubMed] [Google Scholar]
  • 15.Priatel JJ, Utting O, Teh HS. TCR/self-antigen interactions drive double-negative T cell peripheral expansion and differentiation into suppressor cells. J. Immunol. Baltim. Md 1950. 2001;167:6188–6194. doi: 10.4049/jimmunol.167.11.6188. [DOI] [PubMed] [Google Scholar]
  • 16. Crispín JC, Oukka M, Bayliss G, Cohen RA, Van Beek CA, Stillman IE, Kyttaris VC, Juang Y-T, Tsokos GC. Expanded double negative T cells in patients with systemic lupus erythematosus produce IL-17 and infiltrate the kidneys. J. Immunol. Baltim. Md 1950. 2008;181:8761–8766. doi: 10.4049/jimmunol.181.12.8761. **This is the first report of IL-17 producing Double Negative T cells in kidney sections from SLE patients, a finding also present in Lupus mouse models.
  • 17.Lai Z-W, Borsuk R, Shadakshari A, Yu J, Dawood M, Garcia R, Francis L, Tily H, Bartos A, Faraone SV, et al. Mechanistic target of rapamycin activation triggers IL-4 production and necrotic death of double-negative T cells in patients with systemic lupus erythematosus. J. Immunol. Baltim. Md 1950. 2013;191:2236–2246. doi: 10.4049/jimmunol.1301005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Hedrich CM, Rauen T, Crispin JC, Koga T, Ioannidis C, Zajdel M, Kyttaris VC, Tsokos GC. cAMP-responsive element modulator α (CREMα) trans-represses the transmembrane glycoprotein CD8 and contributes to the generation of CD3+CD4−CD8− T cells in health and disease. J. Biol. Chem. 2013;288:31880–31887. doi: 10.1074/jbc.M113.508655. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Koga T, Hedrich CM, Mizui M, Yoshida N, Otomo K, Lieberman LA, Rauen T, Crispín JC, Tsokos GC. CaMK4-dependent activation of AKT/mTOR and CREM-α underlies autoimmunity-associated Th17 imbalance. J. Clin. Invest. 2014;124:2234–2245. doi: 10.1172/JCI73411. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Allgäuer A, Schreiner E, Ferrazzi F, Ekici AB, Gerbitz A, Mackensen A, Völkl S. IL-7 Abrogates the Immunosuppressive Function of Human Double-Negative T Cells by Activating Akt/mTOR Signaling. J. Immunol. Baltim. Md 1950. 2015;195:3139–3148. doi: 10.4049/jimmunol.1501389. [DOI] [PubMed] [Google Scholar]
  • 21.Suárez-Fueyo A, Barber DF, Martínez-Ara J, Zea-Mendoza AC, Carrera AC. Enhanced phosphoinositide 3-kinase δ activity is a frequent event in systemic lupus erythematosus that confers resistance to activation-induced T cell death. J. Immunol. Baltim. Md 1950. 2011;187:2376–2385. doi: 10.4049/jimmunol.1101602. [DOI] [PubMed] [Google Scholar]
  • 22.Talaat RM, Mohamed SF, Bassyouni IH, Raouf AA. Th1/Th2/Th17/Treg cytokine imbalance in systemic lupus erythematosus (SLE) patients: Correlation with disease activity. Cytokine. 2015;72:146–153. doi: 10.1016/j.cyto.2014.12.027. [DOI] [PubMed] [Google Scholar]
  • 23.Wang L, Zhao P, Ma L, Shan Y, Jiang Z, Wang J, Jiang Y. Increased interleukin 21 and follicular helper T-like cells and reduced interleukin 10+ B cells in patients with new-onset systemic lupus erythematosus. J. Rheumatol. 2014;41:1781–1792. doi: 10.3899/jrheum.131025. [DOI] [PubMed] [Google Scholar]
  • 24.Choi J-Y, Ho JH, Pasoto SG, Bunin V, Kim ST, Carrasco S, Borba EF, Gonçalves CR, Costa PR, Kallas EG, et al. Circulating follicular helper-like T cells in systemic lupus erythematosus: association with disease activity. Arthritis Rheumatol. Hoboken NJ. 2015;67:988–999. doi: 10.1002/art.39020. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Xu H, Liu J, Cui X, Zuo Y, Zhang Z, Li Y, Tao R, Li Y, Pang J. Increased frequency of circulating follicular helper T cells in lupus patients is associated with autoantibody production in a CD40L-dependent manner. Cell. Immunol. 2015;295:46–51. doi: 10.1016/j.cellimm.2015.01.014. [DOI] [PubMed] [Google Scholar]
  • 26.Zhang X, Lindwall E, Gauthier C, Lyman J, Spencer N, Alarakhia A, Fraser A, Ing S, Chen M, Webb-Detiege T, et al. Circulating CXCR5+CD4+helper T cells in systemic lupus erythematosus patients share phenotypic properties with germinal center follicular helper T cells and promote antibody production. Lupus. 2015;24:909–917. doi: 10.1177/0961203314567750. [DOI] [PubMed] [Google Scholar]
  • 27.Koga T, Ichinose K, Tsokos GC. T cells and IL-17 in lupus nephritis. Clin. Immunol. Orlando Fla. 2016 doi: 10.1016/j.clim.2016.04.010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Chauhan AK, Moore TL, Bi Y, Chen C. FcγRIIIa-Syk Co-signal Modulates CD4+ T-cell Response and Up-regulates Toll-like Receptor (TLR) Expression. J. Biol. Chem. 2016;291:1368–1386. doi: 10.1074/jbc.M115.684795. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Liu Y, Liao J, Zhao M, Wu H, Yung S, Chan TM, Yoshimura A, Lu Q. Increased expression of TLR2 in CD4(+) T cells from SLE patients enhances immune reactivity and promotes IL-17 expression through histone modifications. Eur. J. Immunol. 2015;45:2683–2693. doi: 10.1002/eji.201445219. [DOI] [PubMed] [Google Scholar]
  • 30. O’Gorman WE, Hsieh EWY, Savig ES, Gherardini PF, Hernandez JD, Hansmann L, Balboni IM, Utz PJ, Bendall SC, Fantl WJ, et al. Single-cell systems-level analysis of human Toll-like receptor activation defines a chemokine signature in patients with systemic lupus erythematosus. J. Allergy Clin. Immunol. 2015;136:1326–1336. doi: 10.1016/j.jaci.2015.04.008. * CyTOFF was used to analyze whole peripheral blood from SLE patients and healthy donors under different stimuli, revealing a role for TLR2 in NF-κB activation in T cells.
  • 31. Sunahori K, Nagpal K, Hedrich CM, Mizui M, Fitzgerald LM, Tsokos GC. The Catalytic Subunit of Protein Phosphatase 2A (PP2Ac) Promotes DNA Hypomethylation by Suppressing the Phosphorylated Mitogen-activated Protein Kinase/Extracellular Signal-regulated Kinase (ERK) Kinase (MEK)/Phosphorylated ERK/DNMT1 Protein Pathway in T-cells from Controls and Systemic Lupus Erythematosus Patients. J. Biol. Chem. 2013;288:21936–21944. doi: 10.1074/jbc.M113.467266. * Authors demonstrate that PP2A, the function of which is increased in SLE T cells, regulates DNA methylation by influencing the phosphorylation of MEK/ERK.
  • 32.Apostolidis SA, Rauen T, Hedrich CM, Tsokos GC, Crispin JC. Protein Phosphatase 2A Enables Expression of Interleukin 17 (IL-17) through Chromatin Remodeling. J. Biol. Chem. 2013;288:26775–26784. doi: 10.1074/jbc.M113.483743. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Isgro J, Gupta S, Jacek E, Pavri T, Duculan R, Kim M, Kirou KA, Salmon JE, Pernis AB. Enhanced Rho-Associated Protein Kinase Activation in Patients With Systemic Lupus Erythematosus: Rock Activation in SLE. Arthritis Rheum. 2013;65:1592–1602. doi: 10.1002/art.37934. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Koga T, Otomo K, Mizui M, Yoshida N, Umeda M, Ichinose K, Kawakami A, Tsokos GC. CaMK4 facilitates the recruitment of IL-17-producing cells to target organs through the CCR6/CCL20 axis in Th17-driven inflammatory diseases. Arthritis Rheumatol. 2016 doi: 10.1002/art.39665. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Kshirsagar S, Riedl M, Billing H, Tönshoff B, Thangavadivel S, Steuber C, Staude H, Wechselberger G, Edelbauer M. Akt-dependent enhanced migratory capacity of Th17 cells from children with lupus nephritis. J. Immunol. Baltim. Md 1950. 2014;193:4895–4903. doi: 10.4049/jimmunol.1400044. [DOI] [PubMed] [Google Scholar]
  • 36.Isgro J, Gupta S, Jacek E, Pavri T, Duculan R, Kim M, Kirou KA, Salmon JE, Pernis AB. Enhanced rho-associated protein kinase activation in patients with systemic lupus erythematosus. Arthritis Rheum. 2013;65:1592–1602. doi: 10.1002/art.37934. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37. Schaffert H, Pelz A, Saxena A, Losen M, Meisel A, Thiel A, Kohler S. IL-17-producing CD4(+) T cells contribute to the loss of B-cell tolerance in experimental autoimmune myasthenia gravis. Eur. J. Immunol. 2015;45:1339–1347. doi: 10.1002/eji.201445064. * Using the experimental autoimmune myasthenia gravis model and the IL-17 KO mice the authors demonstrate the requirement of IL-17 for the loss of B cell tolerance in this model.
  • 38.Detanico T, St Clair JB, Aviszus K, Kirchenbaum G, Guo W, Wysocki LJ. Somatic mutagenesis in autoimmunity. Autoimmunity. 2013;46:102–114. doi: 10.3109/08916934.2012.757597. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Craft JE. Follicular helper T cells in immunity and systemic autoimmunity. Nat. Rev. Rheumatol. 2012;8:337–347. doi: 10.1038/nrrheum.2012.58. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40. Liarski VM, Kaverina N, Chang A, Brandt D, Yanez D, Talasnik L, Carlesso G, Herbst R, Utset TO, Labno C, et al. Cell Distance Mapping Identifies Functional T Follicular Helper Cells in Inflamed Human Renal Tissue. Sci. Transl. Med. 2014;6:230ra46–230ra46. doi: 10.1126/scitranslmed.3008146. * These authors developed a computational tool that allows assessment of TFH cell competency in situ using immunofluorescence.
  • 41.Gigoux M, Shang J, Pak Y, Xu M, Choe J, Mak TW, Suh W-K, et al. Inducible costimulator promotes helper T-cell differentiation through phosphoinositide 3-kinase. Proc. Natl. Acad. Sci. 2009;106:20371–20376. doi: 10.1073/pnas.0911573106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42. Jacquemin C, Schmitt N, Contin-Bordes C, Liu Y, Narayanan P, Seneschal J, Maurouard T, Dougall D, Davizon ES, Dumortier H, et al. OX40 Ligand Contributes to Human Lupus Pathogenesis by Promoting T Follicular Helper Response. Immunity. 2015;42:1159–1170. doi: 10.1016/j.immuni.2015.05.012. ** The authors show the importance of OX40L+ myeloid APCs, which are increased in SLE patients, for the induction of TFH cells. OX40L is overexpressed by myeloid APCs under TLR7 stimulation by immunocomplexes containing RNA and it is sufficient to induce TFH cell molecules in T cells that then become B helpers.
  • 43.Eto D, Lao C, DiToro D, Barnett B, Escobar TC, Kageyama R, Yusuf I, Crotty S. IL-21 and IL-6 Are Critical for Different Aspects of B Cell Immunity and Redundantly Induce Optimal Follicular Helper CD4 T Cell (Tfh) Differentiation. PLOS ONE. 2011;6:e17739. doi: 10.1371/journal.pone.0017739. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Oestreich KJ, Mohn SE, Weinmann AS. Molecular mechanisms that control the expression and activity of Bcl-6 in TH1 cells to regulate flexibility with a TFH-like gene profile. Nat. Immunol. 2012;13:405–411. doi: 10.1038/ni.2242. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45. Ray JP, Marshall HD, Laidlaw BJ, Staron MM, Kaech SM, Craft J. Transcription factor STAT3 and type I interferons are corepressive insulators for differentiation of follicular helper and T helper 1 cells. Immunity. 2014;40:367–377. doi: 10.1016/j.immuni.2014.02.005. Using CD4-cre STAT3-flox mice authors described the importance of STAT3 specifically in TFH differentiation.
  • 46. Ramiscal RR, Parish IA, Lee-Young RS, Babon JJ, Blagih J, Pratama A, Martin J, Hawley N, Cappello JY, Nieto PF, et al. Attenuation of AMPK signaling by ROQUIN promotes T follicular helper cell formation. eLife. 2015;4 doi: 10.7554/eLife.08698. Analyzing different mutant mice and using a bone marrow transplanted model, the authors showed ROQUIN inhibition of AMPK, which allows mTOR activation and is necessary for TFH differentiation.
  • 47. Ray JP, Staron MM, Shyer JA, Ho P-C, Marshall HD, Gray SM, Laidlaw BJ, Araki K, Ahmed R, Kaech SM, et al. The Interleukin-2-mTORc1 Kinase Axis Defines the Signaling, Differentiation, and Metabolism of T Helper 1 and Follicular B Helper T Cells. Immunity. 2015;43:690–702. doi: 10.1016/j.immuni.2015.08.017. *Using Seahorse analysis the metabolic requirements for mouse TH1 and TFH cells under LCMV Armstrong infection conditions were shown. In addition, through different techniques they determine that IL-2/mTOR pathway induces TH1 and blocks TFH differentiation in this model.
  • 48.Ohl K, Tenbrock K. Inflammatory Cytokines in Systemic Lupus Erythematosus. J. Biomed. Biotechnol. 2011;2011:1–14. doi: 10.1155/2011/432595. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Wu M, Yang J, Li X, Chen J. The Role of γδ T Cells in Systemic Lupus Erythematosus. J. Immunol. Res. 2016;2016:2932531. doi: 10.1155/2016/2932531. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Yin S, Mao Y, Li X, Yue C, Zhou C, Huang L, Mo W, Liang D, Zhang J, He W, et al. Hyperactivation and in situ recruitment of inflammatory Vδ2 T cells contributes to disease pathogenesis in systemic lupus erythematosus. Sci. Rep. 2015;5:14432. doi: 10.1038/srep14432. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51.Peterson RA. Regulatory T-cells: diverse phenotypes integral to immune homeostasis and suppression. Toxicol. Pathol. 2012;40:186–204. doi: 10.1177/0192623311430693. [DOI] [PubMed] [Google Scholar]
  • 52.Ohl K, Tenbrock K. Regulatory T cells in systemic lupus erythematosus. Eur. J. Immunol. 2015;45:344–355. doi: 10.1002/eji.201344280. [DOI] [PubMed] [Google Scholar]
  • 53. Kato H, Perl A. Mechanistic target of rapamycin complex 1 expands Th17 and IL-4+ CD4−CD8− double-negative T cells and contracts regulatory T cells in systemic lupus erythematosus. J. Immunol. Baltim. Md 1950. 2014;192:4134–4144. doi: 10.4049/jimmunol.1301859. *Using SLE and healthy donor T cell cultures, in addition to Rapamycin mTOR inhibitor, the authors show that the PI3K/AKT/mTOR pathway is involved in IL-17 expression and deficient Treg function in SLE.
  • 54.Koga T, Ichinose K, Mizui M, Crispín JC, Tsokos GC. Calcium/calmodulin-dependent protein kinase IV suppresses IL-2 production and regulatory T cell activity in lupus. J. Immunol. Baltim. Md 1950. 2012;189:3490–3496. doi: 10.4049/jimmunol.1201785. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55. Koga T, Mizui M, Yoshida N, Otomo K, Lieberman LA, Crispín JC, Tsokos GC. KN-93, an inhibitor of calcium/calmodulin-dependent protein kinase IV, promotes generation and function of Foxp3+ regulatory T cells in MRL/lpr mice. Autoimmunity. 2014;47:445–450. doi: 10.3109/08916934.2014.915954. * This preclinical study shows that inhibition of CaMKIV in the lupus-prone mouse model MRL lpr leads to increased IL-2, expanded Treg numbers and reduced disease. This indicates that both inhibition of CaMKIV or increased IL-2 levels have potential therapeutic use for the treatment of SLE.
  • 56. Mizui M, Koga T, Lieberman LA, Beltran J, Yoshida N, Johnson MC, Tisch R, Tsokos GC. IL-2 protects lupus-prone mice from multiple end-organ damage by limiting CD4−CD8− IL-17-producing T cells. J. Immunol. Baltim. Md 1950. 2014;193:2168–2177. doi: 10.4049/jimmunol.1400977. *Preclinical study confirming that administration of IL-2 in low doses can be a potential treatment for SLE disease. IL-2 helps to increase the number and function of Treg cells and decreased IL-17-producing CD3(+)CD4(−)CD8(−) double-negative T cells.
  • 57. Humrich JY, Spee-Mayer Cvon, Siegert E, Alexander T, Hiepe F, Radbruch A, Burmester G-R, Riemekasten G. Rapid induction of clinical remission by low-dose interleukin-2 in a patient with refractory SLE. Ann. Rheum. Dis. 2015;74:791–792. doi: 10.1136/annrheumdis-2014-206506. **First case report showing efficacy of low-dose IL-2 in a patient with a long-term history of SLE.
  • 58. Spee-Mayer Cvon, Siegert E, Abdirama D, Rose A, Klaus A, Alexander T, Enghard P, Sawitzki B, Hiepe F, Radbruch A, et al. Low-dose interleukin-2 selectively corrects regulatory T cell defects in patients with systemic lupus erythematosus. Ann. Rheum. Dis. 2015 doi: 10.1136/annrheumdis-2015-207776. *Administration of a low dose of recombinant human IL-2 (aldesleukin, 1.5 million IU) for five consecutive days corrected Treg defects, both in vitro and in vivo, and also strongly expanded the Treg population. This study confirms the importance of IL-2 reduction in SLE pathogenesis and explains how low dose IL-2 may induce clinical remission.
  • 59.Banica LM, Besliu AN, Pistol GC, Stavaru C, Vlad V, Predeteanu D, Ionescu R, Stefanescu M, Matache C. Dysregulation of anergy-related factors involved in regulatory T cells defects in Systemic Lupus Erythematosus patients: Rapamycin and Vitamin D efficacy in restoring regulatory T cells. Int. J. Rheum. Dis. 2014 doi: 10.1111/1756-185X.12509. [DOI] [PubMed] [Google Scholar]
  • 60.Lai Z-W, Hanczko R, Bonilla E, Caza TN, Clair B, Bartos A, Miklossy G, Jimah J, Doherty E, Tily H, et al. N-acetylcysteine reduces disease activity by blocking mammalian target of rapamycin in T cells from systemic lupus erythematosus patients: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2012;64:2937–2946. doi: 10.1002/art.34502. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61.Dinesh RK, Skaggs BJ, La Cava A, Hahn BH, Singh RP. CD8+ Tregs in lupus, autoimmunity, and beyond. Autoimmun. Rev. 2010;9:560–568. doi: 10.1016/j.autrev.2010.03.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62.Kim H-J, Verbinnen B, Tang X, Lu L, Cantor H. Inhibition of follicular T-helper cells by CD8(+) regulatory T cells is essential for self tolerance. Nature. 2010;467:328–332. doi: 10.1038/nature09370. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63.Filaci G, Bacilieri S, Fravega M, Monetti M, Contini P, Ghio M, Setti M, Puppo F, Indiveri F. Impairment of CD8+ T suppressor cell function in patients with active systemic lupus erythematosus. J. Immunol. Baltim. Md 1950. 2001;166:6452–6457. doi: 10.4049/jimmunol.166.10.6452. [DOI] [PubMed] [Google Scholar]
  • 64.Alvarado-Sánchez B, Hernández-Castro B, Portales-Pérez D, Baranda L, Layseca-Espinosa E, Abud-Mendoza C, Cubillas-Tejeda AC, González-Amaro R. Regulatory T cells in patients with systemic lupus erythematosus. J. Autoimmun. 2006;27:110–118. doi: 10.1016/j.jaut.2006.06.005. [DOI] [PubMed] [Google Scholar]
  • 65.Jucaud V, Ravindranath MH, Terasaki PI, Morales-Buenrostro LE, Hiepe F, Rose T, Biesen R. Serum antibodies to human leucocyte antigen (HLA)-E, HLA-F and HLA-G in patients with systemic lupus erythematosus (SLE) during disease flares: Clinical relevance of HLA-F autoantibodies. Clin. Exp. Immunol. 2016;183:326–340. doi: 10.1111/cei.12724. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 66.Li X, Kang N, Zhang X, Dong X, Wei W, Cui L, Ba D, He W. Generation of Human Regulatory γδ T Cells by TCRγδ Stimulation in the Presence of TGF-β and Their Involvement in the Pathogenesis of Systemic Lupus Erythematosus. J. Immunol. 2011;186:6693–6700. doi: 10.4049/jimmunol.1002776. [DOI] [PubMed] [Google Scholar]

RESOURCES