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Review
The Yin and Yang of regulatory T cell and therapy progress inautoimmune disease
Yong-chao Qiao a,b, Yan-hong Pan a,c, Wei Ling a, Fang Tian b, Yin-ling Chen a, Xiao-xi Zhang a, Hai-lu Zhao a,b,c,⁎a Diabetic Systems Medicine, Guangxi Key Laboratory of Excellence, Guilin Medical University, Guilin 541004, Chinab Department of Immunology, Xiangya School of Medicine, Central South University, Changsha, Hunan 410078, Chinac Department of Immunology, Faculty of Basic Medicine, Guilin Medical University, Guilin 541004, China
⁎ Corresponding author at: Center for Diabetic SystemsChina.
Article history:Received 8 July 2017Accepted 13 July 2017Available online 2 August 2017
Autoimmune diseases (ADs) are primarily mediated by the failure of immunological self-tolerance. Regulatory Tcells (Tregs) play a critical role in the maintenance of induced tolerance to peripheral self-antigens, suppressingimmoderate immune responses deleterious to the host and preventing the AD development. Tregs and suppres-sive cytokines are homeostatic with effective cells plus pro-inflammatory cytokines in healthy hosts which is de-fined as “Yang”, and ADs are usually induced in case of disturbed homeostasis, which is defined as “Yin”. Indeed,the Yin-Yang balance could explain the pathogenicmechanism of ADs. Tregs not only suppress CD4+ and CD8+Tcells but also can suppress other immune cells such as B cell, natural killer cell, DC and other antigen-presentingcell through cell-cell contact or secreting suppressive cytokines. In Tregs, Foxp3 as an intracellular protein dis-plays a more specific marker than currently used other cell-surface markers (such as CD25, CD40L, CTLA-4,ICOS and GITR) in defining the naturally occurring CD4+ Tregs. Though the precise mechanism for the oppositeeffects of Tregs has not been fully elucidated, the importance of Tregs in ADs has been proved to be associatedwith kinds of immunocytes. At present, the surface marker, frequency and function of Tregs existed conflictsand hence the Tregs therapy in ADs faces challenges. Though some success has been achievedwith Tregs therapyin few ADs both in murine models and humans, more effort should paid to meet the future challenges. This re-view summarizes the progress and discusses the phenotypic, numeric and functional abnormalities of Tregsand is the first time to systematically review the progress of Tregs therapy in kinds of ADs.
Fig. 1. The Yin-Yang balance and immune homeostasis between Tregs (frequency andfunction) plus to suppressive cytokines and effective cells plus to pro-inflammatorycytokines. The homeostatic relationship is defined as “Yang” in healthy hosts and thechanged interaction (increased or decreased) is dedined as “Yin” in autoimmune diseases.
1. Introduction
Autoimmune diseases (ADs) affect almost 20% of the population [1]and are primarily mediated by an abnormal immune response. Whenthe multiple functions were impaired in the immune system in case ofdefending against invasion by pathogens, removing aging or deadcells, identifying and removing aberrant cells due to gene mutation,and preventing the development or growth of tumors [2], an autoim-mune disease usually occurs. To our knowledge, genetic and environ-mental factors are mainly facilitated to this disease and it is difficult toheal completely.
Regulatory T cells (Tregs), a subset of CD4+ T cells, characterizedwith the expression of the transcription factor Foxp3, cytotoxic Tlymphocyte antigen 4 (CTLA-4) and high surface expression ofCD25, have an important role in controlling immune responses,preventing excessive inflammation, enforcing tolerance againstself-antigens and exerting a key homeostatic effect in the immunesystem [3]. And the breakdown of the immune homeostasis may re-sult in inducing auto-antibodies, inflammatory response and tissueinfiltration, which can facilitate the AD development [4]. The sup-pressing responses mediated by the functions of Tregs include cellto cell contact and the synthesis of immunosuppressive cytokines(TGF-β and IL-10) [3]. Studies indicated that Tregs are important inthe pathogenesis of many ADs such as autoimmune hemolytic ane-mia (AHA) [5], autoimmune thyroid disease (AHD) [3,6,7], rheuma-toid arthritis (RA) [8–11], systemic lupus erythematosus (SLE) [10–13], Sjogren syndrome (SS) [14], and systemic sclerosis (SSc) [15–17]. Compromised number and function of Tregs could lead to thedefects of autoimmune tolerance and abnormal immune responses[18,19].
The homeostasis of immune response is maintained between Tregsplus suppressive cytokines and effective cells plus pro-inflammatory cy-tokines in healthy hosts, here we define as “Yang”, and when the ho-meostasis is broken, ADs are usually induced, here we define as “Yin”(Fig. 1). The Yin-Yang balance theory may be an excellent way to ex-plain the pathogenesis of ADs.
Tregs, displayed the powerful immune suppressive capacitywhich could restrict the activation and proliferation of effector Tcells and restore immune tolerance, could be used as a potentmeans of treating ADs [2]. Otherwise, in the development of Treg-based therapies for ADs, the defects in immune tolerance and imbal-ance between Treg and other immune cell were characteristic in thepathology of ADs, so restoring suppressing function through adop-tive transfer therapy of Tregs is a major direction in the treatmentof ADs.
More andmore researchers focus on the Tregs role in ADs, such asthe surface markers, frequency number, suppressing function andtreatment strategy of Treg, however, their studies still displayed dis-crepant outcomes [20]. Therefore, the exploration about the role ofTregs in ADs and the correlation about Tregs and other immunecells, such as effector T cells, B cell, natural kill (NK) cell and mono-nuclear macrophage, possibly give us some insight about the patho-genesis of ADs. In this study, we focus on the correlation about Tregswith cytokines and other immune cells which result in the develop-ment of ADs according to Yin-Yang balance theory, and discuss thestrategy of Tregs therapies used to treat autoimmune and other im-munological disorders.
2. The phenotype and function of different Tregs subsets in ADs
2.1. The phenotype of different Tregs subsets
Some important surface markers and function in Tregs whichdisplayed in Table 1. Tregs characterized with the co-expression of sur-face markers CD3, CD4 and the interleukin-2 (IL-2) α-chain receptor(CD25) (Fig. 2), own immunoregulatory function. And in considerationof the phenotype and function, Tregs displayed a heterogeneous popu-lation [21]. According to the origin of the induction and differentiation,Tregs can be classified into natural Tregs (nTregs) and induced Tregs(iTregs), which generated in the thymus and diffuse to peripheral lym-phoid organs respectively [22]. Otherwise, in the CD4+ T cell popula-tion, suppressive T cells mainly divided into three subtypes, such as IL-10-producing T regulatory 1 cells (Tr1, CD4+CD25lowFoxp3−), TGF-β-
Table 1The known important surface markers and function in Tregs.
Surfacemarker
Receptor Function
CD2 LFA-3 Playing a role in pre-TCR function indouble-negative thymocytes, TCR selectionevents during thymocyte development,TCR-stimulated cytokine production in mature Tcells [47,48] and mediating cell adhesion in bothT-lymphocytes and in signal transduction [49].
TCR-CD3 MHC-II Driving T-cell development, activation, effectorfunctions, and relaying key information fromtheir ligand-binding modules (TCRs) to theirsignaling modules (CD3ce + CD3de andCD3ζζ) and on to the intracellular signalingapparatus [50,51].
CD4 MHC-II CD4 as a receptor for a constant part of MHCclass II molecules interact with the TCR/CD3complex and participate in T-cell activationpossibly through the p56lck tyrosine kinase,which is associated with CD4 at theintracytoplasmic side of the plasma membrane[52].
CD25(IL-2Rα)
CD122(IL-2Rβ)CD132(IL-2Rγ)
IL-2 Three subunits co-consists the IL-2R and theinteraction of IL-2/IL-2R play a key role inT-cell-dependent immune responses byactivating a series of signal pathways [53].
CD45RO/RA Antigen CD45 splice variants RA and RO distinguishnaive (CD45RA+) from central memory andrecently activated (CD45RO+) T cells inperipheral blood [54]. CD45RO expressionrelates to functional memory within the restingCD4+ population, identifying cells that arecapable of proliferating in response to solubleantigen and rapidly produce mRNA encodingIL-4 and IFN-γ [55].
CD28 B7-2 (CD86) CD28 serves as the surface component of anovel signal transduction pathway thatmodulates T-cell lymphokine production andincreases the resistance of T-cell responses tovarious immunosuppressive agents [56].
CD127(IL-7R)
IL-7 Be used to quantitate Treg cell subset whichsupports the use of CD127 as a biomarker forhuman Treg cells [30].
CD154(CD40L)
CD40 The formation and perpetuation of thegerminal center reaction [57] and mediating Bcell responses [58].
CD62L Carbohydrate Mediating CD4+ T cell entry into lymph nodes[59] and enhancing CD4+ T cell activation [60].
CD134(OX40)
TNF As a primary costimulator of T cells, promoteT-cell expansion and restore normalresponsiveness to antigen [61]. A keyco-stimulatory molecule involved in theregulation of CD4 memory T cells [62]. Enhancesurvival of T cells and increase memory T-cellgeneration [63].
CD152(CTLA-4)
B7-1 (CD80) Playing the negative regulatory role in thecontrol of self-reactivity [32,64] and mediatingsignals via the activation of the ubiquitin ligaseItch probably leading to the enhancedubiquitination of Itch target moleculesresulting in inhibition of T cell activity [65].Signals were induced by CTLA-4 act directly onactivated T lymphocytes [66].
CD279(PD-1)
PD-L1 (CD274)and PD-L2(CD273)
PD-1 and its ligands are involved in theinduction of T lymphocyte apoptosis and inregulating the production of nitric oxide,TNF-α, and IL-4. Inducing the deactivation of Tlymphocytes or even other responses that areimportant for maintaining the balance [67].Regulating CD8+ T cells function [68].
TLR PAMP As co-stimulatory receptors to enhanceTCR-induced Teff cell proliferation, survivaland cytokine production [69], block Tregsuppressive function and control immuneresponses [70,71].
Table 1 (continued)
Surfacemarker
Receptor Function
GITR TNF Regulating the CD4+CD25+ T cell subset,enhancing immune responses [72] inhibitingthe suppressive function of Tregs, andtriggering Treg differentiation and expansion[73].
CCR4 CC Tissue-specific lymphocyte homing [74].Support homing of T cells to skin andcutaneous inflammation [75]. Triggerlymphocyte function-associated antigen1-mediated arrest of rolling T lymphocytes[76].
LFA-1 ICAM-1 Playing a critical role in regulatory T cellhomeostasis and as a central receptor incell-to-cell contact mechanisms utilized byTregs to suppress effector cells [77]. Animportant costimulatory signal for T cellreceptor-mediated activation of resting T cells[78].
ICOS ICOSL Regulating CD4 T cell activation and effectorfunction [79] and the adaptive immune system.Controlling Foxp3+ regulatory T-cellexpansion, maintenance and IL-10 production[80].
CCR4, CC chemokine receptor 4; CD, cluster of differentiation; CTLA-4, cytotoxic T lympho-cyte antigen; GITR, glucocorficoid-induced tumor necrosis factor receptor; ICAM-1, inter-cellular adhesion molecule-1; ICOS, inducible costimulator; ICOSL, inducible costimulatorligand; LFA-1, lymphocyte function associated antigen-1; MHC-II, major histocompatibil-ity complex-II; PAMP, pathogen-associated molecular pattern; PD-1, programmed death1; TCR, T cell receptor; TLR, toll-like receptor; TNF, tumor necrosis factor.
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secreting Th3 (CD4+CD25−Foxp3−), and naturally occurring Tregs(CD4+CD25+Foxp3+) [1,23–25].
The CD4+CD25+Foxp3+, as one of the above different types ofTregs, received more attention in recent years [26]. Already some stud-ies have proved that the maintenance of the suppressing function andcell differentiation of Tregs was dependent on the expression of Foxp3which considered as an important transcriptional factor in Tregs [27–29]. Though some questions existed about whether all Tregs areFoxP3+ or whether all FoxP3+ T cells are regulatory, the molecular ofFoxP3 in vivo displayed the best and most specific marker of Tregs upto now.
Low expressed IL-7 receptor (CD127) (Fig. 2) and high expressedFoxP3+ in the subset of CD4+ T cells in peripheral blood, containingthe low level or no CD25, were highly suppressive in functional
Fig. 2. Interaction of surface markers of Tregs with ligands of APC. CD, cluster ofdifferentiation; CTLA-4, cytotoxic T lymphocyte antigen; ICAM-1, intercellular adhesionmolecule-1; ICOS, inducible costimulator; ICOSL, inducible costimulator ligand; LFA-3,lymphocyte function associated antigen-3; MHC-II, major histocompatibility complex-II;PD-1, programmed death 1; TCR, T cell receptor.
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suppressor assays [30]. Thework of Liu,W. et al. displayed the combina-tion of CD4, CD25, and CD127 could form highly purified population ofTregs based on other cell surface markers, which support that surfacemolecule of CD127 could be used as a biomarker for Tregs [30].
Cytotoxic T lymphocyte antigen-4 (CTLA-4) (Fig. 2) is constitutivelyexpressed on CD4+CD25+ Tregs and is suggested to play a role in Tregmediated suppression [31]. The work of Kataoka, H. et al. indicated thatTreg exert in vitro suppressive activity independent of CTLA-4 expres-sion [31]. CTLA-4 played the negative regulatory role in the control ofself-reactivity and was most apparent about the CD4+CD25+CTLA-4+
immunoregulatory T cells in controlling multiple ADs [32].Glucocorticoid-induced tumor necrosis factor receptor (GITR) (Fig.
2) expression had increased in CD4+CD25+ cells, a member of theTNF receptor super family, which plays a functional role about regulat-ing the CD4+CD25+ T cell subset [33]. GITR plays a key role in dominantimmunological self-tolerance maintained by CD4+CD25+ regulatory Tcells and could be a suitable molecular target for preventing or treatingADs [34]. For markers such as CTLA-4 and GITR, not only expressed onTregs, but also expressed on effector T cells, which is problematic fortheir functional role about the immunophenotyping [30]. Other surfacemarkers such as CD103, CD223, CD134, CD122, GITR and toll-like recep-tor (TLR) are not specific in CD4+CD25+ cells and could not representthe suppressing function of Tregs.
Other Tregs subsets, such as CD4+ and CD8+ Tregs: γδ Tregs play animportant role in tissue-associated immunoregulation [35]; CD8+ Tregssuppressor lymphocytes identified in humans could inhibit the prolifer-ation of antigen-specific T cells [36]. Natural killer Tregs as a conservedsubpopulation of lymphocytes could recognize glycolipid antigens in aCD1d context, and exert a key role in regulation of autoimmunity [37].The above Tregs secreted regulatory cytokines such as TGF-β and IL-10 and regulated the immune response. Regulatory B cells, character-ized with their ability to produce autoantibody, possess additional im-mune functions, such as the production of cytokines and the ability tofunction as a secondary APC [38].
2.2. The surface marker function of Tregs in ADs
The key functions of Tregs are to keep the balance of immune re-sponse and tolerance with self-antigen. nTregs (CD4+CD25+FoxP3+-CD127−CD45RA−) [39], activated by IL-2, play the suppressive effectsaccording to cell direct interactions or cytokine secretion mechanisms.Cell direct interactions presumably involve the Tregs with antigen pre-senting cells (APCs) or responding T cells. In the cytokine-independentmechanism, such as the immunosuppressive cytokines, IL-10 and TGF-βinhibit the proliferation of effector T cells and the production of cyto-kineswhich dependent on FoxP3 [21]. The FoxP3,which encodes a tran-scription factor, plays amajor role in governing the functions of Tregs inan autoimmune and inflammatory syndrome in humans and mice.Foxp3–infected CD4+CD25− T cells could significantly reduce the pro-liferation of CD4+CD25− responder T cells when stimulated with CD3mAb, and the suppression effect based on the relationship about the in-hibition of IL-2 production [26]. In addition, the expression of Foxp3 inTregs could inhibit the production of cytokines such as IL-2, IFN-γ, IL-4, and IL-10 [26].
iTregs (CD4+CD25+FoxP3+++CD127−CD45RA−) [39] have nofunction without these antigen stimulated such as during infection,organ transplantation or ectopic expression of non-self antigens and itpromotes the suppression by the synthesis of the suppressive cytokines(IL-10 and TGF-β) in an inflammatory environment [40]. Otherwise,iTregs are also activated and expanded through TGF-β, IL-10 or IL-2 [22].
IL-10 has an intimate connection with a series of immune suppres-sive effects, such as the inhibition of APC function, induction of anergy,differentiation of Tregs, and control of the expansion of other T cell pop-ulations [41]. TGF-β, as a multifunctional cytokine circulated in plasmawith a biologically inactive form, ownedmultiple functions, such as reg-ulation of cell proliferation and extracellular matrix production.
Otherwise, TGF-β could enhance immunosuppressive function throughmaintaining the expression of Foxp3 of CD4+CD25+ Tregs.
The surface marker of Tregs, CD122 (IL-2Rβ chain) (Fig. 2), is re-sponsible for IL-2 signal transduction [42] and is used by the receptorsof both IL-2 and IL-15 [43]. The high expression about CD122 in Tregscould induce higher binding of IL-2, IL-15, or both. Preferential bindingof IL-2 may reduce the availability of this cytokine to effector cells,thus reducing their expansion. IL-15 has been shown to reduce the sus-ceptibility of T cells to activate induced cell death [44]. Therefore, in-creased expression of CD122 may provide regulatory cells with asurvival advantage, allowing immune regulation to persist. Tregs, pref-erentially bind with IL-2, could reduce the availability of this cytokineto effector T cells, and then reduce their expansion. Some results haveproved that IL-15 could reduce the T cells susceptibility and inducedcell death [44]. Therefore, CD122 highly existed in Tregs, could providea survival advantage and allow immune regulation to persist (Table 1).
Themainmechanism of suppression response of Tregswas to inhibitthe production of IL-2 by responder T cells and interestingly, Tregs havebeenmanifested constitutive expression of CTLA4 (CD152) both inmiceand in humans. Fallarino et al. proved that CD4+CD25+ cells, over ex-pressing CTLA-4 by treatment with antibody to CD3, initiated trypto-phan catabolism in dendritic cells (DCs) through a CTLA-4-dependentmechanism in mouse [45]. So CD4+CD25+ Tregs could implementtheir suppressive response either by directly suppressing T cells or indi-rectly through modulation of APC function [45]. Otherwise, the work ofChen, W. et al. found that the cross-linking of CTLA-4 induces TGF-βproduction, which may in part contribute to the down regulation of Tcell activation. CTLA-4, through TGF-β, may serve as a counterbalancefor CD28 costimulation of IL-2 and CD4+ T cell activation [46]. Other-wise, Kingsley, C. I. et al. speculated that there may be a commonmech-anism of action linking CTLA-4 and IL-10 [41].
3. The interactions between Tregs and other immunocytes
The net correlation existed in series of immunocytes including Tregs,Th1, Th2, Th17, B cell, mononuclear macrophage, NK cell, CD8+ T celland DC that exert their role by the synthesis of immunosuppressive cy-tokines or pro-inflammatory cytokines, which displayed in Fig. 3.
3.1. Tregs and Th cells
Th1 cells are necessary to clear intracellular pathogens and Th2 cellsare important for clearing extracellular organisms. The Th1 driven re-sponses, mediated by Th1 cell [secreting IL-2, interferon γ (IFN-γ) andtumor necrosis factor α (TNF-α)] and macrophages (secreting IL-1, IL-6, IL-12 and TNF-α) which was defined as cellular immunity, whileTh2-driven responses (secreting IL-4, IL-5, IL-6, IL-10 and IL-13),which antibodies and/or immune complexes served as the main medi-ators that was defined as humoral immunity [81]. The balance of Th1and Th2 was aimed to keep the cytokines homeostatic in ADs. Just asthe homeostasis between Th1 and Th2, the Tregs and Th17 (secretingIL-17, IL-23) were also cross regulated and a variety of molecularswitches or mediators can influence the reciprocal differentiation be-tween Tregs and Th17 cells.
TGF-β not only could facilitate the development of Tregs, but alsocontribute to the induction of Th17 based on the presence of a pro-in-flammatory cytokine (IL-6 or IL-1) [81]. Other researchers, Veldhoen,M. et al., have proved that Treg can be substituted by TGF-β1 togetherwith the pro-inflammatory cytokine IL-6 which promotes Th17-cell dif-ferentiation; otherwise, the process is amplified by IL-1β and TNF-α. IL-6 plays an important role in driving the transcription of Th17 lineage-specific genes through activating signal transducer and STAT3which in-hibits the Foxp3 expression and the generation of Tregs [82]. Thoughthey could not detect a role for IL-23 in the Th17 cells differentiation,they confirmed its important role in their survival and expansion [82].More than that, their data indicated that TGF-β1 subverted Th1 and
Fig. 3. The interactions among series of immune cells. CD4+ Tregs could suppress Th1, Th2 and B cells by the synthesis of immunosuppressive cytokines (TGF-β and IL-10), and suppressmononuclear macrophage, NK, CD8+ and dendritic cells by cell-cell contact. IL-6 secreting from dendritic cells and Th2, in combination with Treg-secreting TGF-β promotes thedevelopment of Th17 cells. IL-17 secreting from Th17 could facilitate the differentiation of APC and B cells. IFN-γ from Th1 cells may cause the proliferation and cytokine production ofmononuclear macrophages and suppress the Th2 and Th17 cells. IL-4 from Th2 cells suppresses the proliferation of Th1 and Th17 cells. IL-12 from APC could promote the proliferationof CD8+ T cells. The red arrows display inhibition and the black arrows indicate promotion, respectively.
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Th2 differentiation for the generation of Th17 cells in the presence of IL-6 [82].
Mangan, P. R. et al. confirmed that, Th17 cells which tailored to spe-cific classes of pathogens almost evolved to provide adaptive immunityand TGF-β contributed to the development as an important cytokine[83]. The development of Th17 cells has also been linked to IL-23, anIL-12 cytokine family member which shares with IL-12 a common sub-unit, otherwise, the receptors of IL-23 and IL-12 share a subunit (IL-12Rβ1, IL-23R and IL-12Rβ2) to confer receptor responsiveness andTGF-β can up-regulate the expression of IL-23R which conferred re-sponsiveness to IL-23 [83].
Bettelli, E. et al. proved that IL-6 completely inhibited the expressionand generation of TGF-β-induced Foxp3+ Tregs in mice and IL-23 is notthe differentiation factor for the generation of Th17 cells [84]. On thecontrary, IL-6 plus to TGF-β could induce the differentiation of patho-genic Th17 cells from naive T cells (Fig. 3), which indicated that effectorT cell and Tregs may differentiate from the same precursor T cells thatdepend on the balance of cytokines present in the environment [84].Otherwise, their results demonstrated a dichotomy which the genera-tion of Th17 could induce autoimmunity and Tregs may prevent the in-jury of autoimmune tissue [84].
3.2. Tregs and NK cells
NK cells play an important role in the innate immune systemwhichnot merely exert cell to cell contact-mediated cytotoxicity against in-fected cells or tumor cells, but also play regulatory role through promot-ing or suppressing the functions of other immune cells by the synthesisof chemokines and cytokines [85]. Several studies have proved thatTregs could suppress NK cell effector functions in vitro [86,87], andSmyth, M. J. et al. have indicated that themechanism could directly sup-press NK cell function via the natural-killer group 2, member D
(NKG2D) pathways through the activated Tregs in vivo. Otherwise,the relief of the suppression of Tregs could significantly enhance thefunctional activity of NK cells in the environment of activating IL-12 cy-tokine, which has the role for enhancing the NKG2D pathway of NK cellactivation [88]. The suppressive effect of Tregs exerting on NK cells cy-totoxicity is dependent on the secreting cytokine TGF-β and Smyth, M.J. et al. has proved that the ability of soluble TGF-β could reduce NKcell cytotoxicity and perforin gene transcription [89]. Trzonkowski, P.et al. examined the cytotoxic activity in the cultures of peripheralblood mononuclear cells (PBMC) and separate CD8+ T cell or NK cellsmixed with Treg respectively and found that the production of IFN-γ,perforin and the cytotoxic activity of CD8+ T cell or NK cells were de-creased in the presence of Tregs. Tregs-producing IL-10 in the culturesmay mix the results, and when add the anti-IL10 mAb into the cultures,the outcomes did not change, which indicated that Treg exert the sup-pressing effect by inhibiting both CD8+ T cell and NK lymphocyte cyto-toxic activities in a direct cell-to-cell interaction [86].
3.3. Tregs and antigen-presenting cells (APCs)
APC includes monocytes/macrophages, B cells and DCs. Monocytes/macrophages have an important role in the chronic inflammatory pro-cess and the destruction of some tissues through the production ofpro-inflammatory cytokines (TNF-α and IL-6), and some studies havereported that Tregs could inhibit the proinflammatory properties ofmonocytes/macrophages [90]. The suppressive effects on monocytes/macrophages were exerted directly by CD4+CD25+ Tregs and then sig-nificantly affect innate or adaptive immune responses. CD4+CD25+
Tregs own the ability of modulating the monocytes through changingthe activation of the cells, and leading to the lowed production of pro-inflammatory cytokine and the hampered function. Low cytokineswere produced in monocytes co-culture with CD4+CD25+ Tregs, but
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large amounts of pro-inflammatory (TNF-α, IFN-γ and IL-6) and sup-pressive (IL-10) cytokines were producedwhenmonocytes co-culturedwith CD4+CD25− T cells [90]. Monocytes after CD4+CD25+ Treg treat-ed, then re-purified after co-culture, and stimulatedwith LPS, could sig-nificantly suppress their capacity about producing TNF-α and IL-6 [90].Otherwise, the phenotype of monocytes displayed limited up-regula-tion of HLA class II, CD40 and CD80, and down-regulation of CD86after pre-culture with CD4+CD25+ Tregs, which the change of pheno-type had functional consequences.
DCs played an important role in the initiation and regulation of im-mune responses as the professional bone marrow-derived APCs, andthe diversity of phenotype and function is related with their stage ofmaturation and/or to their myeloid or lymphoid origin [91]. TGF-βand IL-10, secreted from Tregs, could influence the differentiation andfunction of DC [92]. DC may control a series of T cell mediated immuneresponses by presenting antigens and providing co-stimulatory signalsand pro-inflammatory cytokines to T cells, moreover, T cells could in-crease the function of the DC through cell-cell contact and co-stimulato-ry receptor-ligand pairs [93]. The work of Cederbom, L. et al. Found thatCD4+CD25+ Tregs could down regulated the expression of the costim-ulatory molecules CD80 and CD86 of DC, which suggested that Tregscould exert their suppressive function through the down-regulation ofco-stimulatory molecules [93].
Tregs could inhibit the production of autoantibody [94] with a con-tact- or death-independent manner by direct inhibition of B cell-medi-ated IgM production or indirect of CD4+ T cell. Tregs co-cultured withIL-2 could sustain the B cell and secret the detectable levels of IgM[95]. Thework ofWeingartner, E. et al. observed that some secreted fac-torsmay influence the suppression of IgM secretion, and suggested thatthe Tregs suppression of B cells appeared to be contact-dependent [95].They supposed that TGF-β secreted by Tregs exert the potential sup-pressing function of B cell. Previous work indicated that CD4+CD25+
Tregs could act directly on B cells, and through co-cultured B cellswith activated CD4+CD25+ Tregs, the proliferation of B cells was signif-icantly suppressed. The reason was due to the increased cell deathwhich was caused by a cell to cell contact manner and up-regulatedthe perforin and granzymes of Tregs, but notmediated by Fas-Fas ligandpathway [96]. The work of Iikuni, N. et al. also proved that natural Tregscould inhibit the activity of B cells in vitro and in vivo by cell contact-mediated mechanisms which directly suppress the autoantibody of Bcells [97].
3.4. Tregs and CD8+ T cells
CD8+ cytotoxic T lymphocytes (CTLs) normally have the functionabout the protection against viruses and elimination of tumor cells,and result in the damage of abnormal or infected cells by TCR/CD8 rec-ognition ofMHC-I presented by target cells. Then damage them throughthe ability to produce the cytotoxic proteins (granzymes and perforin)and pro-inflammatory cytokines (IFN-γ and TNF), and induce the Fassignaling triggering apoptosis pathways. CTLs also play a key point inADs and contribute to the induction, progression, pathogenesis and pro-tection of ADs [98–101]. CTLs have awell-documented role in the devel-opment of diabetes and are the most abundant pancreas-infiltratingcells during insulitis to mediate beta cell death in early onset of type 1diabetes [102]. Autoreactive clones of CTLs found in the peripheralblood infiltrated into pancreas and cause disease [103]. It was foundthat the incidence of diabetes was reduced from 77% to 16% in theperforin-deficient mice, backcrossed with the nonobese diabetesmouse strain, and the disease onset was markedly delayed (medianonset of 39.5 versus 19 weeks) in the latter which indicated that CTLscontribute to the progression of this disease [104].
Tregs have an intimate connection with CTLs and suppress CTLsthrough signal pathways of cell-cell contact. Previous study provedthat CD30, as a member of the TNFR family upregulated on antigen-in-duced Tregs, play a key role for Tregs in suppressing CD8+ memory T
cells recall through the presence of CD30 on Tregs and the CD30/CD30L interaction [105]. Programmed death-1 (PD-1) as one of the pro-totypic inhibitory receptors negatively regulate the proliferation and ac-tivation of T cell and exert the suppressive functions through thebinding with the ligands (PD-L1 or PD-L2) [106,107]. Treg suppressthe activity of CD8+ T cells depend on the expression and interactionof PD-1 expressed on Tregs and PD-1 ligand expressed on CD8+ Tcells. Park, H. J. et al. found that the binding of PD-1 and PD-L1 inhibitedTCR signaling and caused the deterioration of T cell immune responseagainst chronic viruses [108]. Otherwise, T cell immunoglobulin andmucin domain 3 (Tim-3) expressed in Tregs play the suppressed func-tion by recognizing the ligand galectin-9 [109]. CD4+CD25+ T cells,through inhibiting IL-2 production and up-regulation of CD25 expres-sion, could suppress the proliferation and producing-IFN-γ of CD8+ Tcells, which was mediated by a cell-cell interaction (Fig. 3) and in theabsence of APC [110]. CD4+ Tregs from persistently infected micecould suppress IFN-γ production of CTLs and treatment mice withanti-GITR antibody significantly increase the production of IFN-γ,which indicated GITR played an important suppressive response in im-mune system [111]. Another signal pathways about Tregs suppressingthe CTLs are the binding of OX40/OX40L [112] or B7-1/CTLA-4 [113]expressed on CTLs and Tregs respectively.
4. Tregs for AD therapy
4.1. Type 1 diabetes mellitus (T1DM)
T1DM as a chronic inflammatory disease characterized with the Tcell-mediated destruction of insulin-producing β-cells and could leadto the development of kinds' complications. The abnormalities of T cellphenotype and function are potential targets of immune interventionsto preserve insulin-producing β-cells [114]. The therapy of Tregs pro-videsmanypotential advantages such as specific and lastingdampeningof inflammation [115]. More effort focused on the role of Tregs as apromising therapeutic tool for the treatment of ADs, and distinguishesthe phenotype and function of the different subsets of Tregs.
Due to the adoption of the different phenotypes of Tregs in the re-search of T1DM, many conflicts about the frequency and function existin current studies (Table 2). In general, it is widely believed that in theconcept of defining the phenotypes of the naturally occurring CD4+
Tregs used as preventing ADs, Foxp3 displays a more accurate markerthan currently used cell-surface molecules including CTLA-4, CD45RB,CD25 and GITR, which could not completely discriminate betweenTregs and activated, effector, or memory T cells [26].
The therapy with Tregs has been succeeding in both animal modelsand humans. Stumpf, M. et al. displayed that adoptively transferredwith Treg cells from wild type mice could significantly reduce the inci-dence of mice diabetes [116]. Marek-Trzonkowska, N. et al. provedthat Tregs infusion in 12 T1DM children treated with autologous ex-panded ex vivo Tregs with one year follow-up, bring about the increaseof Tregs number and C-peptide levels in peripheral blood, and the re-sults indicated that the repetitive administration of Tregs could prolongsurvival of β-cells in T1DM [117]. Bluestone, J. A. et al. expanded Tregsfrom patients with T1D and retained their T cell receptor diversity anddemonstrated enhanced functional activity, then the T1DM patients re-ceived ex vivo-expanded autologous polyclonal Tregs. The resultsshowed that the Tregs was significantly increased in recipients andretained a broad Treg phenotype long-termwhich support the develop-ment of the Treg therapy [118].
At present, several attempts has been exerted with the aim of re-es-tablishing immune tolerance through the induction or direct infusion ofTregs, which include glutamic acid decarboxylase (GAD) injection [119,120], autologous umbilical cord blood transfusion [121,122], stem celleducator therapy [123], anti-CD3 therapy [124,125], and hematopoieticstem cell transplantation (HSCT) [126,127]. Some of above therapieshas displayed efficacy which significantly increase the suppressive
Table 2The frequency and function of CD4+ Tregs in human autoimmune diseases.
Type 1 diabetes mellitus (T1DM)Lawson, J. M. et al.[153]
CD4+CD25hi
CD4+CD25hiFoxp3+
CD4+CD25+CD127−/loFoxp3+
Normal frequencyNormal suppressivefunction
Luczynski, W. et al.[154]
CD4+CD25hi
CD4+CD127lowDecreased frequency
CD4+CD25hiCD127low Normal frequencyJin, Y. et al. [155] CD4+CD25+
CD4+CD25hiIncreased frequency
Kukreja, A. et al. [156] CD4+CD25+ Decreased frequencyBadami, E. et al. [157] CD4+CD25+CD127−Foxp3+ Decreased frequencyAlonso, N. et al. [158] CD4+Foxp3+ Normal frequencyLindley, S. et al. [159] CD4+CD25high Normal frequency
Normal suppressivefunction
Brusko, T. et al. [160] CD4+CD25+CD127−/loFoxp3+ Normal frequencyNormal suppressivefunction
McClymont, S. A. etal. [161]
iTreg:CD4+CD25+CD127−/loFoxp3+
Increased iTreg frequency
Glisic, S. et al. [162] CD4+CD25high Increased suppressivefunction of iTreg
Marwaha, A. K. et al.[163]
rTreg:CD45RA+CD25+Foxp3low
aTreg:CD45RA−CD25+Foxp3high
Normal frequency ofrTreg and aTreg
Haseda, F. et al. [164] aTreg:CD45RA−Foxp3high
Increased frequency ofaTreg;Decreased suppressivefunction of aTreg
Schneider, A. et al.[165]
CD4+CD25high Normal suppressivefunction
Putnam, A. L. et al.[166]
CD4+CD25high Normal frequencyNormal suppressivefunction
Zahran, A. M. et al.[167]
CD4+CD25high
CD4+CD25highFoxp3+Decreased frequency
CD4+CD25+ Normal frequency
Rheumatoid arthritis (RA)Li, N. et al. [9] CD4+CD25+Foxp3+ Decreased frequencyFessler, J. et al. [168] CD4+Foxp3+CD28− Increased frequencyCao, D. et al. [169] CD4+CD25bright Decreased frequencyLawson, C. A. et al.[170]
CD4+CD25high Normal frequencyNormal suppressivefunction
Toubi, E. et al. [171] CD4+CD25+ Increased frequencyMottonen, M. et al.[172]
CD4+CD25+ Normal frequency
Cao, D. et al. [173] CD4+CD25bright Normal frequencyNormal suppressivefunction
Liu, M. F. et al. [174] CD4+CD25+ Normal frequencyEhrenstein, M. R. etal. [175]
CD4+CD25+ Normal frequencyNormal suppressivefunction
Lee, J. H. et al. [182] CD4+CD25+ Decreased frequencyYang, X. Y. et al. [183] CD4+CD25+ Decreased frequencyBonelli, M. et al. [184] CD4+Foxp3+ Increased frequencyMiyara, M. et al. [24] CD4+CD25bright Decreased frequencyValencia, X. et al.[185]
Barath, S. et al. [191] CD4+CD25highFoxP3+ nTreg: DecreasedfrequencyIncreased suppressivefunction
Venigalla, R. K. et al.[187]
CD4+CD25+Foxp3+ Normal frequency
Zhao, S. S. et al. [192] CD4+CD25+Foxp3+
CD4+CD25highDecreased frequency
CD4+CD25+CD127low/− Normal frequencyHabibagahi, M. et al.[193]
CD4+CD25high
CD4+Foxp3+Decreased frequency
Sjogren syndrome (SS)Miyara, M. et al. [24] CD4+CD25bright Decreased frequencyIchikawa, Y. et al. [194] CD4+CD45RA+ Decreased frequencyAlunno, A. et al. [195] CD4+CD25−GITR+ Increased frequencyGottenberg, J. E. et al.[196]
CD4+CD25low Normal frequencyNormal suppressivefunction
Khan, S [17]. CD4+CD25brightFoxP3+ Decreased frequency
1065Y. Qiao et al. / Autoimmunity Reviews 16 (2017) 1058–1070
function of Tregs and decreased daily dose of insulin requirement, butthe others did not achieve the objectives.
Though some potential concerns regarding the safety of Tregs im-munotherapy existed such as possibly bring about undesired adverseevents [115], it is an encouraging treatment for the T1DM patients.
4.2. Rheumatoid arthritis (RA)
RA, as a chronic inflammatory autoimmune disease, is characterizedwith unclear etiology includingprogressive and destructive polyarthritisassociated with serological evidence of auto-reactivity which lead topersistent and progressive synovitis [8]. The infiltration of T cell, B celland monocyte and the proliferation of synoviocyte and endothelial cellcontribute to the hyperplasia of the synovium [21] and the abnormalityabout the frequency and function of Tregs play a key role in initiationand progression of this disease.
Though the frequency and function of Tregs are controversial inpresent (Table 2). The possible reasons of these conflicts may be ex-plained by differences in disease stage and therapy and in the differentphenotypic definition of naturally occurring Tregs in the above men-tioned studies [128]. However, the suppressive function of Tregs univer-sally got more approved andmany studies have been proved that Tregshave an important regulatory mechanism in RA [8,129–131].
Tregs therapy has also implemented in controlling this disease andachieved encouraging results. Morgan, M. E. et al. transferred Tregsinto mice which exhibited arthritis symptoms and found disease pro-gression markedly slowed. The results indicated that Tregs could beused for the treatment of systemic, antibody-mediated ADs, such as RA[132]. Autologous stem cell transplantation (ASCT) as a treatment for se-vere refractory autoimmune disease could restore the normal frequencyand function of Tregs in juvenile idiopathic arthritis (JIA) patients [133].Several promising new approaches inducing immune tolerance hasbeen studied in humans, such asmucosal peptide-specific immunother-apy, immunomodulatory neuropeptides, andrenomedullin, urocortin,tolerogenic DCs and genetic manipulation of T cells [134].
Several treatment strategies with the aim of Treg modulation areguessed that may be available therapeutics in RA such as anti-TNF-αblockade, anti-IL-6 therapy, CTLA-4-Ig and anti-CD3 therapy [135]. Oth-erwise, IL-27may be a novel and promising therapeutic agent for RA pa-tients [136]. For RA, more effort needs to focus on whether the Tregscould be used as a therapeutic method in humans, not only decreasethe severity and progression of this disease but also to cure establisheddisease.
4.3. Systemic lupus erythematosus (SLE)
SLE as a heterogeneous inflammatory chronic autoimmune disordercharacterized with multiple organ damages and abnormal immune re-sponse, and was breakdown of tolerance to self-nuclear, cytoplasmicand cell surface molecules [137–139]. The etiology of SLE is controver-sial and some predisposing factors have been found, such as genetic, en-vironmental, infections, and hormonal factors [137], otherwise, Tregsplay an important role to suppress autoreactive effector T cells in theimmune system and got more focus in recent years.
Though the data about the frequency and surfacemarkers of Tregs inSLE were inconsistent (Table 2), the suppressive function existed in SLEwas decreased and was got general consent. The discrepancy existed inthese studies, one side, because the difference in detection surfacemarkers, gating strategies in flow cytometry, methodology and theTregs of healthy controls which displayed a large range in previousstudies (0.5%–12%). Otherwise, the unstable disease activity status con-tributes to the change of Tregs, because the increase of Tregs in activedisease state was more significant than remission state [131].
Therapy with Tregs in SLE has also made great success both in miceand human. In the clinical translation of Tregs-based immunotherapy ofSLE, the amounts of purified CD4+CD25+Foxp3+ Tregs were adoptivelytransferred into lupus-prone (NZBxNZW) F1 mice and the maintainingdisease remission were explored. The results indicated that Tregs couldprolong the interval of remission induced by conventional cytostaticdrugs and this study offered important information and a first proof-of-concept for the feasibility of a Treg-based immunotherapy in themainte-nance of disease remission in SLE [140]. In the clinical trials with Tregs-based immunotherapy of SLE patients, low-dose IL-2 therapy with theaim of expanding and activating Tregs population could control ADs andinflammation. More importantly, the above study provided that low-dose IL-2 therapy could expand Tregs in human SLE patients [141,142].
4.4. Sjogren syndrome (SS)
SS as one of the most common ADs, characterized with lymphocyticinfiltration of all exocrine glands (especially salivary glands), disruptingthe glandular epithelium and inducing dry mouth and eye symptoms(xerostomia and xerophthalmia) [143]. Nearly 1–3% in general popula-tions were affected andmore significant inwomen. Though the patholo-gy of SS in not clear, generally the genetic disposition and environmentalfactors were thought to play an important role [143,144].
The frequency and function of Tregs in SS are also conflicting andonly a few researches focus on the role about Tregs in SS patients(Table 2). To our knowledge, therapy with Tregs got achievement
1066 Y. Qiao et al. / Autoimmunity Reviews 16 (2017) 1058–1070
successfully in mice but not put into use in humans. In mouse with thy-mectomy, lacrimal gland-draining cervical LN Tregs were purified andused to prevent dacryoadenitis, and the results indicated that the lacri-mal gland-protective Tregs exert a key role in preventing lacrimal glandautoimmunity [145]. Otherwise, the difficult about therapy is that therole of Tregs is still unclear in SS. The change of Tregs was variable de-pend on the activity of the autoimmune process, and the self- or exoge-nous antigens in target organs in SS may escape from immunologicalsurveillance and clearance. More effort should be paid about Tregs inthe pathogenesis of SS which need deserve further investigation.
4.5. Autoimmune thyroid disease (ATD)
ATD characterized with reactivity to self-thyroid antigens that wereconsidered as damaged inflammatory or anti-receptor, and wassubdivided into Hashimoto's thyroiditis (HT) and Graves' disease (GD)[3,7]. In ATD patients, peripheral tolerance to self-antigens and the acti-vation of T cell were controlled by Tregs. The pathogenesis of ATD waselusive which has a significant relationship with a series of geneticand environment factors.
Among the published studies, the number and function of Tregs werediscrepant (Table 2). The conflicting resultsmay be explained that lackingof the differentiation between GD and HT patients, the isolation methodof the Tregs, the inconsistent surface markers of Tregs, the discrepantFCM analysis, the cell-culture durations and the methods of measuringproliferation which result in the diversity. Otherwise, this discrepancymay influence the future therapeutic strategy. If the defect existed inTregs frequency, the increased Tregs number methods are reasonableby drug treatment or cell therapy, and if the defect existed in Tregs func-tion, the receiving either molecular or cellular stimulation would recoverthe function of normal Tregs [3]. As far as we know, there still is no effecttherapeutic strategies used in humans and the options of current thera-pies are limited to antithyroid medications, radioactive iodine ablation,and surgical treatment that accompanied with high risk. More effortshould be paid on the challenge of therapy in ATD patients.
4.6. Autoimmune hemolytic anemia (AHA)
In humans, AHA is the first recognized organ-specific and antibody-mediated autoimmune disease inwhich the red blood cells are destroyedprematurely by tissuemacrophages because of the inducing of antibodiesagainst the patient's own red blood cells [5,146]. Tregs may play an im-portant role in AHA and more effort about Tregs has been paid in thepathogenic mechanism and therapeutic schemes in human patients.
Though some conflicts existed about the frequency and function ofTregs (Table 2), the defects of Tregs has been got unanimous recognitionand the alternative strategy about restoring Tregs defects or imbalanceshas been put into practice. The Tregs therapy was successfully used inmurine model. Mqadmi, A. et al. treated with anti-CD25 antibody tocontrol the immunization of RBCs of C57/Bl6 mice, which significantlyincreased the incidence of AHA from 30% to 90%. And purify the Tregsfrom spleens and adoptive transfer into naive recipients which couldprevent the induction of autoantibody production [147]. At present,the therapies in AHA patients include taking immunosuppressivedrugs along with transfusion or splenectomy, which mainly controlbut not cure this disease [147].
Tregs exert the key role in controlling the ADs and the immunother-apeutic potential of Tregs could be an efficient therapeutic strategy fortreatment of AHA in humans.
4.7. Systemic sclerosis (SSc)
SSc as a systemic autoimmune disease characterized with excessiveextracellular matrix deposition and damage of small blood vessels, inwhich widespread vasculopathy and immunological abnormalitieswere induced by the fibrosis of the skin and organs and the damage of
endothelial cells [148–150]. SSc is usually divided into two clinical sub-sets: one is diffuse cutaneous SSc characterized with the rapidly pro-gressive fibrosis of the skin and visceral organs, and the other islimited cutaneous SSc characterized with the limited skin fibrosis andthe low prevalence of internal organ involvement [148].
The pathogenesis of SSc is still not clear, but the circulating autoan-tibodies mediated inflammatory processes play a key role in the skinand visceral organs (heart, lungs, or kidneys), otherwise, Tregs immunehomeostasis has been proved to have a big role in the fate of SSc throughthe inducing the peripheral tolerance of potentially pathogenic autoim-mune response [149]. Contradictions still existed about the frequencyand function of Tregs (Table 2) though some efforts have been madein exploring the importance in autoimmune system which attribute tothe different active-degree of the disease, different analysis strategies,samples fromdifferent inflamed tissue and inconsistent surfacemarkersin Tregs and so on.
At present the therapeutic options are still limited, and prostanoidsand calciumantagonists are recommended for SSc-related digital vascu-lopathy attacks in patients, otherwise, immune suppressive therapieswith corticosteroids, methotrexate, azathioprine, cyclosporine or cyclo-phosphamide possibly slow the progression of SSc [151]. Extracorporealphotochemotherapy is another good choice for the SSc patients [152].To our knowledge, the Tregs therapy has not been put into practice.The Tregs-directed therapy with the aim of T cell immune homeostasisis attempting and the treatment couldmodify both number and activityof Tregs in SSc patients. Persistent research focused on the role of Tregsabout proportional and functional change in SSc patients and Tregs me-diated therapy could be a new therapeutic option in the future.
5. Conclusions
The homeostasis is kept between Tregs plus suppressive cytokinesand effective cells plus pro-inflammatory cytokines in hosts, and whenthe balance is broken the ADs are possibly induced. Tregs exert the abil-ity of suppressing the immune response and play an important role inADs. Foxp3 as an intracellular protein displays a more specific markerthan currently used other cell-surface markers (such as CD25, CD40L,CTLA-4, ICOS and GITR) in defining the naturally occurring CD4+ Tregswhich could prevent autoimmune disease. Tregs not only suppressCD4+ and CD8+ T cells but also can suppress other immune cells suchas B cell, natural killer cell, DC and other antigen-presenting cell throughcell-cell contact (such as CTLA-4, ICOS, GITR and LAG-3) or secretingsuppressive cytokines (such as IL-10 and TGF-β). Though some successhas been achievedwith Tregs therapy in fewADs both inmurinemodelsand humans, more effort should paid to meet the future challenges.
Take-home messages
• The homeostasis is kept between Tregs plus suppressive cytokinesand effective cells plus pro-inflammatory cytokines in hosts, andwhen the balance is broken the ADs are possibly induced.
• Foxp3 as an intracellular protein displays a more specific marker thancurrently used other cell-surfacemarkers in defining the naturally oc-curring CD4+ Tregs which could prevent autoimmune disease.
• Tregs not only suppress CD4+ and CD8+ T cells but also can suppressother immune cells such as B cell, natural killer cell, DC and other an-tigen-presenting cell through cell-cell contact or secreting suppres-sive cytokines.
• Though some success has been achieved with Tregs therapy in fewADs both in murine models and humans, more effort should paid tomeet the future challenges.
Funding
This study was supported by the National Natural Science Founda-tion of China (81471054).
1067Y. Qiao et al. / Autoimmunity Reviews 16 (2017) 1058–1070
Conflicts of interest
None.
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