systemic lupus erythematosus ( sle ) is a severe systemic autoimmune disease and , as such , is characterized by a loss of self - tolerance .
the etiology of sle is not well defined , but genetic , hormonal , and environmental factors , as well as immune disorders , are likely implicated . during sle , inflammation leads to damage of various tissues , including the joints , skin , kidneys , heart , lungs , blood vessels , and brain .
dysregulation of various components of the immune system can be observed at different stages of disease development , but hyperactivity of b cells , leading to excessive production of multiple autoantibodies ( autoab ) , is one of the major immunological stigmata of sle .
indeed , sle is characterized by the production of antinuclear autoab ( e.g. , autoab specific for chromatin ) and by the formation of immune complexes , which contribute to tissue damage .
deposits of immune complexes in organs such as kidneys lead to subsequent inflammation through the activation of the complement system and the recruitment of inflammatory cells .
the presence of autoab is an absolute prerequisite for the development of lupus nephritis   and , interestingly , we demonstrated that pathogenic autoab can be locally produced by plasma cells , which have homed to inflamed kidneys of lupus mice .
b cells and derivatives ( plasma cells ) are thus considered at the center of sle pathogenesis and this is supported by the observation of a high frequency of plasma cell precursors in the blood of children with sle .
furthermore , an increase of circulating plasma cells in lupus patients is correlated with disease activity .
the generation of ab can occur via the extrafollicular or the germinal center ( gc ) responses .
the extrafollicular response leads to short - lived plasma cells , which do not go through the affinity maturation process .
in contrast , the gc is the theater of intense cell collaboration between gc b cells and follicular helper t cells ( tfh ) leading to the differentiation of long - lived plasma cells harboring high antigen - specificity .
interestingly , lupus autoab are high affinity , somatically mutated , and class - switched immunoglobulin ( ig)g   indicating t and b cell collaboration   and intense gc activity .
therefore , it is likely that a dysfunction in b cell differentiation mechanisms occurs in lupus , leading to excessive numbers of autoreactive plasma cells .
it is particularly attracting and plausible to envisage that a dysregulation of tfh could be the underlying key factor . in this review
, we succinctly expose recent understanding in tfh biology ( described in detail elsewhere ; see   for review ) , in order to introduce important molecular factors involved in tfh differentiation , regulation , and function .
we then give an overview of the aberrant expression and/or function of such key players in lupus patients , and we highlight their potential as therapeutic targets .
the generation of high affinity ab requires t / b interactions that mainly occur in gc .
tfh cells represent a distinct subset of cd4 t cells involved in gc formation and specialized in providing help to b cells to differentiate into plasma cells or memory b cells .
tfh express high levels of cxc chemokine receptor type 5 ( cxcr5 ) , pd-1 ( programmed death-1 ) , icos ( inducible t cell co - stimulator ) , and the regulator transcription factor bcl6 ( b cell lymphoma 6 ) , which provide excellent markers for their identification .
moreover , secretion of high levels of il-21 is a critical characteristic of tfh cells .
tfh are generated after immunization or infection following the interaction of naive cd4 t cells with dendritic cells ( dc ) within the t cell zone of secondary lymphoid organs ( slo ) .
signals provided by dc induce the expression of a myriad of proteins ( transcription factors , surface molecules , and cytokines ) that are essential for tfh generation , migration , and function .
in fact , tfh differentiation is a multistage process ( figure 1 ) , which can be sequentially defined as follows : ( i ) naive cd4 t cells are activated by dc ( thanks to the mhc - peptide complex / tcr interaction ) in the t cell zone and become immature tfh ( also called pre - tfh ) ; ( ii ) newly generated pre - tfh then migrate to the interfollicular zone , where cognate interactions with b cells allow the final maturation step ; ( iii ) these mature tfh reach the gc in which tfh - gc b cell interactions will favor isotype class switch , somatic hypermutations , and affinity maturation .
the initial priming of cd4 t cells requires cognate interactions and costimulatory signals delivered by dc through cd40 , cd80/86 , icosl , and ox40l ( table 1 ) .
cd28 ( that binds cd80/86 ) was shown to be essential to tfh development as mice deficient for cd28 display cd4 t cells that fail to upregulate cxcr5 and ox40 , leading to disrupted gc formation .
in addition , upregulation of ox40l on dc following cd40-induced maturation allows cxcr5 expression by ox40 t cells .
moreover , icos signaling leads to an increased expression of the transcription factors bcl6 and ascl2 ( achaete - scute homologue-2 ) .
the latter promote both the reciprocal cxcr5 upregulation and ccr7 downregulation on activated cd4 t cells , which then become pre - tfh [ 12 , 13 ] . in turn
, bcl6 induces the expression of icos , pd1 , cd40l , and sap ( slam- ( signaling lymphocytic activation molecule- ) associated protein ; critical for t - b interaction ) .
cytokines secreted by dc also play a pivotal role in pre - tfh development ( table 1 ) .
il-6 , a dc - derived proinflammatory cytokine , has been demonstrated to be the main soluble factor driving tfh differentiation in mice . in humans
, il-12 has been shown to be the key cytokine that promotes tfh - like cell differentiation [ 15 , 16 ] .
if , in the initial work , neither il-6 nor il-21 were described as being able to promote tfh differentiation , a recent study suggests that human plasmablasts produce il-6 , which is responsible for the subsequent differentiation of naive cd4 t cells into b cell helpers cxcr5icosbcl6il-21 t cells .
il-21 is required for tfh function but it is also an important factor for tfh generation   and , interestingly , both il-6 and il-12 are potent inducers of il-21 expression in mice   and humans , respectively .
as il-21 is an autocrine cytokine for pre - tfh generation , further studies are required to better clarify individual cytokine contributions .
cytokine signaling involves the subsequent activation of janus kinase - stat ( signal transducer and activator of transcription ) signaling pathway .
stat3 is a major signaling molecule for il-6 and il-21 [ 20 , 21 ] , whereas il-12 signaling occurs through stat4 activation .
however , il-12-induced expression of il-21 by human cd4 t cells is compromised in patients with functional stat3 deficiency , suggesting that il-12 ability to promote il-21-producing cd4 t cells is predominantly stat3 dependent . moreover ,
altogether , these data suggest that the stat3 signaling pathway plays an important role in tfh differentiation and subsequent b cell help . during this first step of the tfh differentiation process , both cell surface interactions and cytokine signaling play a crucial role in bcl6 induction .
bcl6 requirement for tfh development was reported in 2009 by 3 independent groups [ 2426 ] .
indeed , bcl6 is a master regulator for tfh lineage commitment as its expression can inhibit th1 , th2 , and th17 differentiation .
bcl6 expression is influenced by il-6 and il-21 via stat1 and stat3 signaling and by icos - pi3k ( phosphoinositide 3-kinase ) signaling .
moreover , bcl6 expression is controlled by a complex regulatory network of activating factors ( see   for detailed review ) such as basic leucine zipper transcriptional factor atf like ( batf ; ) , transcription factor 1 ( tcf-1 ; ) , lymphoid enhancer - binding factor ( lef-1 ; ) , and b cell oct - binding protein 1 ( bob1 ; ) , while forkhead box protein o1 ( foxo1 ; ) negatively regulates bcl6 expression .
thanks to cxcr5 expression enhancement and ccr7 downregulation ( table 2 ) , pre - tfh cells migrate to the b cell follicle in response to a cxcl13 gradient and their interaction with antigen - specific b cells at the t - b border contributes to final tfh differentiation .
indeed , the lower frequency of tfh cells in b cell - deficient mice suggests that b cells are also important for the generation of tfh cells . at this stage ,
b cells act as the major antigen - presenting cells ( apc ) for primed - tfh that will then fully differentiate into gc tfh cells .
mature tfh and b cells that have formed stable t - b conjugates move together into the follicle to form gc .
stable t - b conjugate formation requires interaction between icos on tfh and icosl expressed by b cells , as well as slam interactions ( table 2 ) .
sap , which is the adaptor signaling protein downstream of slam , was demonstrated to be important for stabilizing cognate t - b interactions .
indeed , sap - deficient cd4 t cells have an impaired capacity to stably interact with cognate b cells , resulting in a failure to induce b cell clonal expansion .
moreover , patients with x - linked lymphoproliferative disease ( xlp ) , an immunodeficiency resulting from mutations in the sh2d1a gene which encodes sap , harbor humoral defects characterized by hypogammaglobulinemia and reduced numbers of tfh .
b cells thus play a key role in the tfh maturation step by both acting as apc and stabilizing tfh - gc b cell interactions through icosl and slam . the major function of tfh is to enhance high affinity memory ab responses following migration to gc . in the follicles ,
tfh - gc b cell crosstalk involves cd40l , il-21 , pd-1 , and baff ( b cell activating factor ) ( table 3 ) .
the signal delivered through interaction between pd-1 on tfh and pd - l1 expressed by gc b cells is crucial for gc b cell survival .
il-21 production by tfh directly regulates b cell proliferation and class - switch , and the il-21 pathway has been identified as a critical component of the memory b cell response as secondary antigen - specific igg responses are impaired in il-21r - knockout mice .
baff is a cytokine that belongs to the tumor necrosis factor ( tnf ) ligand family and its receptors are bcma ( b cell maturation antigen ) , taci ( transmembrane activator and calcium modulator and cyclophilin ligand interactor ) , and baff receptor 3 ( br3 ) .
baff is produced by stromal cells in the slo and involved during gc development by influencing icosl expression on b cells and thus regulating the ability of gc b cells to promote tfh expansion .
moreover , baff production by tfh is critical for the survival of high affinity b cell clones . in summary ,
molecules that have been described to play a key role in tfh biology do not display equivalent functions .
some are necessary for tfh migration from the t cell zone to the gc , others are absolutely required for their development or function , and finally some of them are essential for tfh maintenance and survival ( tables 13 ) . considering the important role of tfh cells in humoral immunity ,
a balance between stimulatory and inhibitory mechanisms regulating their function is required for immune homeostasis . however , while signals important for tfh development are clearly defined nowadays , little is known about mechanisms involved in their regulation .
the coinhibitory pd-1/pd - l1 pathway can limit tfh expansion and consequently the humoral ig response .
similarly , it was demonstrated that the inhibitory receptor b and t lymphocyte attenuator ( btla ) suppresses gc b cell development and subsequent igg responses by inhibiting il-21 production by tfh cells   ( table 3 ) .
recently , the existence of regulatory t cells ( treg ) able to inhibit gc responses was described .
this subset of regulatory t cells of thymic origin was first identified in mice   and named tfr ( follicular regulatory t cells ) .
they express typical markers of both tfh cells ( bcl6 , cxcr5 , pd-1 , and icos ) and classical treg ( foxp3 ) ; they localize in the gc and possess suppressive activity .
a cd4 t cell population coexpressing foxp3 , bcl6 , and cxcr5 was also visualized in human tonsils .
indeed , the mir-17~92 cluster was shown to promote tfh differentiation by repressing pten ( phosphatase and tensin homolg ) , phlpp2 ( pleckstrin homology domain and leucine - rich repeat protein phosphatase ) ( phosphatases that inhibit bcl6 expression through interfering with pi3k signaling ) , and ror ( retinoic acid - related orphan receptor  ) expression [ 42 , 43 ] .
on the other hand , mir-10a negatively regulates tfh differentiation by directly inhibiting bcl6 expression .
similarly , mir-146a , a microrna that is highly expressed in tfh cells , was recently described as a negative regulator of tfh cell numbers .
mir-146a deficiency leads to accumulation of both tfh and gc b cells , likely due to enhanced icosl and icos expression on gc b cells and tfh cells , respectively . finally ,
il-2 signaling is also an important negative regulator of tfh differentiation by inducing stat5-dependent expression of blimp1 , a bcl6 repressor [ 4648 ] .
moreover , high il-2 production by th1 cells induces t - bet , which in turn inhibits bcl6 expression and tfh differentiation .
the main function of tfh cells consists in regulating the clonal selection of gc b cells and providing b cells with signals for ig production , isotype switching , and somatic hypermutations . as abnormal activation of b cells and autoab production
are central to autoimmune diseases , such as lupus , altered tfh differentiation , function , and regulation were suspected to play a role in lupus pathogenesis .
first hypotheses regarding the role of tfh cells in sle development are based on studies using mice deficient for roquin1 ( a negative regulator of icos mrna stability ) in which an excessive number of tfh cells and gc reactions and high levels of il-21 are associated with a lupus - like phenotype [ 50 , 51 ] .
other evidences come from studies on il-21 , the main cytokine produced by tfh , in lupus mice .
high il-21mrna as well as elevated il-21 serum levels were described in bxsb.yaa mice , which develop an sle - like disease .
the use of a fusion protein consisting in the il-21r linked to the fc domain of a mouse igg2a ( il-21r.fc , which therefore binds to il-21 and prevents activation of its receptor ) revealed a complex biphasic role of il-21 in this mouse model as it increases or diminishes the disease severity depending of the stage of the disease at the time of il-21 neutralization ( at early or late stages ) .
this could be related to the action of il-21 on b cells but also on t cell responses . in lupus mrl / lpr mice ,
activated cd4 t cells secrete 10 times more il-21 than control mice   and il-21r deficiency leads to reduced numbers of tfh cells .
in addition , abundant tfh - like cells are located outside the gc where they support extrafollicular b cell differentiation and plasmablast maturation in bxsb - yaa and mrl - fas lupus mice [ 56 , 57 ] . in the latter and contrary to what was expected ,
the extrafollicular pathway was shown to be the most important way to generate hypermutated autoabs . however , there is no evidence to date supporting the involvement of such extrafollicular response in human sle .
tfh cells are located in slo ; therefore the major problem encountered in studies of human tfh is that lymphoid tissues of lupus patients can not be easily accessed , making it difficult to identify tfh cells and to determine whether the generation or function of these cells is dysregulated .
first studies were based on the enumeration of cd4cxcr5 in peripheral blood as gc tfh counterparts . using this strategy , it was shown in human sle that circulating tfh cells ( ctfh ) defined as cd4cxcr5pd-1 and/or icos t lymphocytes are expanded in lupus patients and their presence correlates with a more severe disease phenotype [ 5964 ] .
morita et al . have described a circulating population in healthy donors that shares common phenotypic and functional characteristics with tfh cells from gc .
moreover , they distinguished three subclasses , that is , tfh17 , tfh2 , and tfh1 , defined according to the expression of the ccr6 and cxcr3 chemokine receptors : tfh17 cells are cxcr3ccr6 cells whereas tfh2 cells are cxcr3ccr6 cells and tfh1 cells are cxcr3ccr6 cells .
tfh17 and tfh2 cells were identified as able to provide help to b cells via il-21 production , resulting in igm and igg secretion , whereas tfh1 have limited helper functions . however , icos expressing tfh1 are able to help memory b cells ( but not naive b cells ) to produce ab following influenza vaccination .
moreover , morita and colleagues showed that patients with juvenile dermatomyositis displayed a profound skewing of ctfh cells towards tfh2 and tfh17 cells that correlated with disease activity , suggesting that an altered balance of tfh subtypes contributes to human autoimmunity .
recently , the differential expression of icos , pd-1 , and ccr7 interestingly allowed distinguishing three memory ctfh subsets defined as activated cells ( icospd1ccr7 ) or quiescent cells ( icospd1ccr7 and icospd1ccr7 ) [ 67 , 68 ] . in sle patients ,
the ccr7pd1 subset is indicative of active tfh differentiation and its overrepresentation is associated with elevated autoab titers and high disease activity . by analyzing cxcr3 and ccr6 expression , we also interestingly described an altered phenotype of ctfh cells characterized by the enhanced frequency of b cell helper tfh2-like cxcr3ccr6 cells and a decreased frequency of cxcr3ccr6tfh1-like cells ( not able to provide b cell help ) in lupus patients with an active disease .
aberrant expression and/or function of tfh - related molecules are associated with lupus - like disease in mice [ 54 , 70 ] . similarly , in lupus patients , numbers of molecules involved in tfh generation and/or regulation
cd40/cd40l pathway plays an essential role in the initial phase of tfh development ( t - dc interaction in the t cell zone ; figure 1 , ) and function ( tfh - gc b cell crosstalk in the gc ; ) .
interestingly , cd40l was found to be constitutively expressed at abnormally high levels on t cells ( but also on b cells and monocytes ) from lupus patients [ 72 , 73 ] .
furthermore , cd4 t cells from female lupus patients , which overexpressed cd40l mrna , were able to promote autologous b cell stimulation and autoab production .
icos - mediated pi3k signaling is absolutely required for tfh differentiation , for tfh migration into the follicle , and also for tfh maintenance .
pten acts as a negative regulator of the pi3k signaling pathway , leading to the inhibition of bcl6 expression and tfh differentiation .
interestingly , pten expression is significantly decreased in sle b cells ; however , to the best of our knowledge , its expression in lupus cd4 t cells ( especially tfh ) has not been investigated yet .
icos expression has been found to be enhanced in cd4 t cells from lupus patients compared to healthy donors [ 78 , 79 ] and icos levels were higher in patients with nephritis than in those without nephritis .
moreover , infiltrated icos t cells were shown to be in close contact with b cells in lupus kidneys .
interaction between ox40l ( on dc ) and ox40 ( on activated cd4 t cells ) is also important for tfh development .
ox40 expression by lupus peripheral blood cells was found to be predominantly restricted to memory cd45ro cd4 t cells and its levels correlated with disease activity .
moreover , ox40 has also been found to be highly expressed in kidneys of patients with lupus nephritis .
importantly , the upstream region of the ox40 gene contains a single risk haplotype for sle , which is correlated with increased expression of ox40 mrna and protein .
finally , it was recently shown that ox40 signal promotes , ex vivo , the generation of tfh - like cells that are functional b cell helpers .
elevated levels of il-6 have been found in the serum and in the urine of active sle patients [ 8587 ] .
the increased frequency of il-6-producing peripheral blood mononuclear cells ( pbmc ) correlates with disease severity / activity and treatment response . raised expression of gp130 ( one of the two subunits of the il-6 receptor ) has been found on cd4 t cells and b cells from patients with active sle , while an important reduction in the gp130 expression by b lymphocytes was observed upon immunosuppressive treatment leading to milder disease activity .
factors responsible for the constitutive expression of il-6 in sle have not been elucidated yet .
serum il-21 levels were found to be elevated in patients with sle [ 69 , 90 ] , especially in patients with lupus nephritis , and to correlate with disease severity .
the real - time pcr analysis of skin biopsies taken from 3 lupus patients also revealed that il-21 transcripts were significantly increased compared to control individuals .
furthermore , the percentages of cd4 t cells producing il-21 are significantly enhanced in lupus patients .
finally , polymorphisms within the il-21r and the il-21 genes have been reported and may confer risk for sle : a polymorphism in il-21r ( namely , rs3093301 ) was found to associate with lupus in 2 independent cohorts , a genetic association of two snps located in intronic regions of the il-21 gene ( rs2221903 and rs907715 ) was described , and the variant allele rs2055979a of the il-21 gene was recently found to be associated with increased il-21 levels . regarding baff , lupus sera have been shown to contain elevated levels of this cytokine and those levels correlate with both anti - dsdna titers [ 9698 ] and disease activity .
finally , it has been reported that il-2 production ( which inhibits tfh differentiation ) upon tcr stimulation is impaired in sle t lymphocytes [ 100 , 101 ] .
this lower il-2 production could be explained by imbalanced expression between the transcription factors camp response element ( cre ) binding protein ( creb ) and the cre - modulator ( crem ) , which , respectively , enhance and suppress the il-2 gene transcription .
stat3 , which is activated by cytokines such as il-6 and il-21 , binds to the bcl6 promoter leading to high levels of bcl6 expression and is thus important for tfh differentiation .
t cells from patients with sle display increased levels of total and phosphorylated stat3 [ 103 , 104 ] . reduced expression of mir-146a ( a negative regulator of tfh development ) has been reported in pbmc from sle patients   and seems to correlate with disease activity . moreover
, a genome - wide association study has highlighted a variant , that is , rs2431697 , in an intergenic region between pttg1 ( pituitary tumor - transforming 1 ) and mir-146a , associated with lupus susceptibility .
interestingly , the risk allele of this snp correlates with a diminution of mir-146a levels . to date , the analysis of frequency and/or functionality of tfr cells in an autoimmune context has not been reported . however , although there may be some discrepancies due to variations in phenotype analysis , peripheral regulatory t cells ( cd4cd25 t cells ) seem to play a role in human lupus pathogenesis .
several studies reported that a decreased number of treg might contribute to the pathogenesis [ 108111 ] , but there were conflicting data regarding treg function in lupus patients .
the in vitro suppressive activity of these cells was found to be defective in some reports [ 111 , 112 ] but other studies showed that the suppressive activity of highly purified treg from lupus patients is not altered .
it has been proposed that defective suppression in lupus could be attributed either to a higher sensitivity of treg to fas - mediated apoptosis in an sle context   or to a lower susceptibility of effector t cells to treg suppression .
finally , it has been shown that ifn- production by lupus apcs might be responsible for altered treg functionality .
data obtained from various lupus mouse models have already highlighted how blockade of signaling pathways involved in tfh generation could lead to disease improvement .
the administration of a blocking icos - l specific monoclonal ab ( mab ) to lupus nzb / w mice interrupted tfh cell development leading to a decrease of autoab levels and glomerulonephritis [ 115 , 116 ] .
similar results were obtained in mrl / lpr lupus mice displaying a genetic deletion of icos .
blockade of the cd40l - cd40 signaling pathway also led to the reduction of lupus symptoms in different mouse models [ 117 , 118 ] .
treatment of mrl / lpr lupus mice with a neutralizing anti - il-6r mab has favorable effects on renal function and leads to a reduction of anti - dsdna ab levels . in nzb / w mice , chronic administration of anti - il-6 or anti - il-6r mab improves survival and reduces the progression of proteinuria and anti - dsdna levels [ 120 , 121 ] . in lupus - prone nzb / w and mrl / lpr mice ,
raised levels of baff are detected at the onset of the disease   and treatment with either taci - ig or br3-ig is effective at preventing clinical disease and ameliorating renal injury .
regarding il-21 , its neutralization using il-21r.fc showed an improvement of biological and clinical signs of the disease in mrl / lpr lupus mice and bxsb - yaa mice [ 53 , 54 ] .
moreover , the administration of ab specific for the il-21r to mrl / lpr mice significantly reduced anti - dsdna ab titers and igg deposits in the kidneys when compared to control mice . in nzb / w mice , such il-21r blocking even allowed reversing nephritis and halting disease progression in mice with preexisting lupus . by using a mirna - delivery approach via bacteriophage
ms2 virus - like particles , pan and colleagues recently showed that restoring the loss of mir-146a was effective in abolishing autoab production and delaying sle progression in lupus - prone mice .
interestingly also , treatment with the small molecule called stattic ( an inhibitor initially reported to block the phosphorylation , dimerization , and nuclear translocation of stat3 in tumor cells ) delayed the onset of proteinuria and reduced both anti - dsdna autoab and inflammatory cytokine levels in mrl / lpr lupus mice .
several therapeutic tools targeting tfh biology already exist and even if their direct effect on tfh development has not been evaluated , some of them were shown to improve the disease .
tocilizumab , a humanized mab specific for the -chain of the il-6 receptor ( which prevents il-6 from binding to membrane bound and soluble il-6 receptors ) , has been recently tested in sle patients with promising results .
interestingly , tocilizumab therapy in rheumatoid arthritis patients leads to a significant reduction in circulating tfh cell numbers and il-21 production .
belimumab , a human mab that binds soluble baff , therefore inhibiting recognition by baff specific receptors has been tested in patients and results from phase iii clinical trials have demonstrated the safety profile and efficacy in controlling lupus in a broad range of patients .
belimumab is the first biologic to meet its primary endpoint in a phase iii clinical trial for lupus patients and it was approved by the us food and drug administration in 2011 . among other potential therapeutic candidates ,
are those targeting t - b interactions , such as idec-131 ( anti - cd40l ab ) , amg 557 ( anti - icosl ab ) , abatacept ( ctla4-ig ) , or targeting cytokines such as atr-07 ( anti - il-21r ab ) , nnc0114 - 0006 ( anti - il-21 ab ) , atacicept ( taci - ig ) , and small molecules inhibiting cytokine signaling pathways ( tofacitinib , a jak - stat inhibitor ) ( figure 2 ) .
although prognosis in sle has improved markedly in the last 40 years , a better knowledge of the disease remains of prime importance to develop more potent and specific treatments .
new targeted therapies designed to block pathways involved in disease pathogenesis are on the horizon .
one promising option could be to specifically target factors involved in the generation of plasma cells responsible for the production of pathogenic autoab in lupus .
tfh play a critical role in b cell activation and differentiation , and recent data have evidenced their involvement in lupus pathogenesis .
signals required for tfh development may thus represent interesting targets in order to reduce tfh numbers ( and/or to correct the altered proportion of tfh subsets ) or to qualitatively and/or quantitatively modulate their function .
another exciting therapeutic option consists in enhancing the negative molecular and cellular regulators of tfh , such as mirna or tfr .
 systemic lupus erythematosus ( sle ) is a chronic autoimmune disease characterized by b cell hyperactivity leading to the production of autoantibodies , some of which having a deleterious effect . reducing autoantibody production 
 thus represents a way of controlling lupus pathogenesis , and a better understanding of the molecular and cellular factors involved in the differentiation of b cells into plasma cells could allow identifying new therapeutic targets . 
 follicular helper t cells ( tfh ) represent a distinct subset of cd4 + t cells specialized in providing help to b cells . 
 they are required for the formation of germinal centers and the generation of long - lived serological memory and , as such , are suspected to play a central role in sle . 
 recent advances in the field of tfh biology have allowed the identification of important molecular factors involved in tfh differentiation , regulation , and function . 
 interestingly , some of these tfh - related molecules have been described to be dysregulated in lupus patients . in the present review , 
 we give an overview of the aberrant expression and/or function of such key players in lupus , and we highlight their potential as therapeutic targets . 
1. Introduction
2. T
3. Evidences Supporting the Involvement of T
4. Molecules and/or Cytokines Involved in T
5. Targeting T
6. Concluding Remarks