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. 2019 Jan 21;234(8):12442–12450. doi: 10.1002/jcp.28092

Decreased number and impaired function of type 1 regulatory T cells in autoimmune diseases

Xi Jia 1, Tianyu Zhai 2, Bing Wang 1, Qiuming Yao 1, Qian Li 1, Kaida Mu 3,✉, Jin‐an Zhang 3,✉
PMCID: PMC13484160  PMID: 30666652

Abstract

Type 1 regulatory T (Tr1) cell is a special type of T regulatory cells with surface molecular markers such as lymphocyte‐activation gene 3 and CD49b. A key property of Tr1 cells is the capability to produce high‐level interleukin 10 (IL‐10) upon activation, in a FOXP3‐independent manner. The immunosuppressive function of IL‐10 producing Tr1 cells has been extensively studied for many years. Autoimmune diseases (AIDs) are conditions in which the immune system breaks down and starts to attack the body. AIDs include inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis (MS), type 1 diabetes mellitus, Greaves' disease, and so forth. In recent years, more and more studies have documented that the number of Tr1 cells is decreased and the function is inhibited in a variety of AIDs, among which MS is the most widely studied. The protocol for engineering Tr1 cell therapy has been established and is gradually being used in clinical practice in recent years. Tr1 cell therapy has been proven to be safe and effective, but it is mainly involved in myeloid leukemia, graft versus host disease currently. Its therapeutic role in AIDs still needs to be further explored. In this study, we will summarize the research advances of Tr1 cells in AIDs, which will provide useful information for treating AIDs through Tr1 cell therapy in the future.

Keywords: autoimmune diseases, IL‐10, immunotolerance, multiple sclerosis, type 1 regulatory cells

Abbreviations

AhR

aryl hydrocarbon receptor

AID

autoimmune diseases

GVHD

graft versus host disease

HIF1‐α

hypoxia inducible factor 1α

HSCT

hematopoietic stem cell transplantation

IRF1

interferon regulatory factor 1

JAK

janus kinase

MHC

major histocompatibility complex

Nfil3

nuclear factor IL‐3

ROR‐α

orphan nuclear receptor‐α

STAT

signal transducer and activator of transcription

Tr1

type 1 regulatory T cell

1. INTRODUCTION

Autoimmune diseases (AIDs) are multifactorial diseases in genetically susceptible individuals, mainly including inflammatory bowel disease (IBD), rheumatoid arthritis (RA), multiple sclerosis (MS), type 1 diabetes mellitus (T1DM), Greaves' disease (GD), and so on (Dominguez‐Villar & Hafler, 2018). Immunity imbalance and autoimmune attacking, mainly orchestrated by T and B lymphocytes, are believed to contribute to disease pathogenesis and promote disease progression (Dominguez‐Villar & Hafler, 2018; Feng et al., 2015). CD4+ T cells exert critical roles in mediating adaptive immunity, and its number and functional abnormality are important factors in the pathogenesis of AIDs (Feng et al., 2015). After contacting with an antigen major histocompatibility complex (MHC), naïve CD4+ T cells can differentiate into regulatory T (Treg) cells and different effector cell subsets including T helper 1 (Th1), Th2, follicular helper, and Th17 cells, under the microenvironment with various inflammatory factors (Hori, Nomura, & Sakaguchi, 2003). Effector T cells and their cytokines are important components in the immune system but their hyperfunction and autoantigen attacks can damage host tissues and lead to AIDs (Wahren‐Herlenius & Dorner, 2013). The main function of Treg is to inhibit the excessive activation of effector T cells and prevent immune damage to the body (Wahren‐Herlenius & Dorner, 2013). Decreased number and dysfunction of Treg cells are often found in AIDs (Tao et al., 2017). Among cell surface molecular markers, Treg cell is often defined as CD4+CD25+FOXP3+CD127low T‐cell subgroup (Dominguez‐Villar & Hafler, 2018). In recent years, Treg cell subsets have been discovered, including type 1 regulatory T (Tr1) cells, Th3 cells, CD8+CD28− T cells and human leukocyte antigen (HLA)‐E‐specific CD8+ T cells (Jiang et al., 2010; Tao et al., 2017). Unlike Treg cells, Tr1 cells are often independent of FOXP3 and CD25 (Mascanfroni et al., 2015). Like other effector T cells, Tr1 cells can express FOXP3 instantaneously after activation, but do not express FOXP3 persistently (Andolfi et al., 2012). Moreover, the expression level of FOXP3 in Tr1 cells is much lower than that in general FOXP3+ Treg cells (Andolfi et al., 2012). Previous studies have not confirmed the characteristic biomarkers of Tr1 cells, except for the characteristic secretion of interleukin 10 (IL‐10; Roncarolo et al., 2006). Until recently, it is found that lymphocyte‐activation gene 3 (LAG3) and integrin ɑ2 subunit (CD49b) is specifically expressed on Tr1 cells both in human and mice, which can be used as the defined cell surface signatures (Gagliani et al., 2013). Functionally, as the subset of Treg cells, Tr1 cells also have immunosuppressive functions, including the secretion of inhibitory cytokines such as IL‐10 and transforming growth factor‐β (TGF‐β), cell contact inhibition, cytolysis, and metabolic disruption (Andolfi et al., 2012; Gregori, Goudy, & Roncarolo, 2012; Gregori & Roncarolo, 2018; Roncarolo, Gregori, Bacchetta, & Battaglia, 2014). Because the special immunosuppressive function and the newly discovered surface maker facilitate the research, Tr1 cells have gained extensive attention as a research hot spot of AIDs in recent years. The quantity, function, and clinical application of Tr1 cells have been studied in a variety of AIDs in preclinical and clinical models, such as MS, IBD, GD, TIDM, RA, psoriasis, Hashimoto's thyroiditis (HT), and systemic lupus erythematosus (SLE; Alfen et al., 2018; Kim et al., 2018; Le Buanec et al., 2011; Mielle et al., 2018; Vitales‐Noyola et al., 2018; Zohar et al., 2018). Defects in the frequency and function of Tr1 cells are present in many AIDs, suggesting that IL‐10 producing Tr1 cells are associated with anti‐inflammatory and disease protection. Increasing number and function of Tr1 cells in patients or promoting the body to produce more IL‐10 may be a new strategy for treating AIDs. In this study, we will summarize the research achieves of Tr1 cells in AIDs, which will be beneficial to provide useful information for future researchers.

2. BIOLOGICAL CHARACTERISTICS AND FUNCTIONS OF TR1 CELLS

FOXP3‐independent Treg cells mainly consist of two heterogeneous subgroups, Tr1 cells and iTr35 cells. It is reported that CD4+CD25−LAG3+ T cells account for approximately 2% of CD4+CD25− T‐cell population in the spleen, but it should be noted that CD4+CD25−LAG3+ T cells do not fully represent Tr1 cells (Okamura et al., 2009; Okamura, Yamamoto, & Fujio, 2018). The coexpression of LAG3 and CD49b is the necessary condition for defining IL‐10 producing FOXP3 negative peripheral‐induced CD4+ Tr1 cells. Tr1 cells are derived from naive precursors and therefore similar with Th1 and Th2 cells, they are inducible cells and can be differentiated in vitro and in vivo (Pot, Apetoh, & Kuchroo, 2011; Volchenkov, Karlsen, Jonsson, & Appel, 2013). In human body, Tr1 cells are developed extrathymically because high‐affinity interactions with autopeptide‐MHC ligands expressed in the thymus are not essential for the development of Tr1 cells (Okamura et al., 2018). Moreover, the response of Tr1 cells to TCR stimulation is hypoproliferative and is in a relatively stable state (Okamura et al., 2018). The currently known major factors for stimulating Tr1 cell differentiation are IL‐10 and IL‐27 (Batten et al., 2008; Comi, Amodio, & Gregori, 2018). IL‐10 mainly stimulates Tr1 cell differentiation in vivo via the activation of janus kinase 1 (JAK1), signal transducer and activator of transcription 3 (STAT3), and p38 mitogen‐activated protein (MAP) kinase signal pathways (Brockmann et al., 2017; Comi et al., 2018; Locafaro et al., 2017; Schmetterer & Pickl, 2017). However, IL‐27 can stimulate Tr1 cell differentiation both in vivo and in vitro (Vigne et al., 2017). IL‐27 induces the differentiation of mouse Tr1‐like cells by activating STAT1 and STAT3, thereby promoting LAG3 expression and IL‐10 production by transcription factors Egr‐2 and Blimp1 (Vigne et al., 2017). In addition, there are many other stimulation factors, including AhR, hypoxia inducible factor 1α (HIF1‐α), c‐Maf, nuclear factor IL‐3 (Nfil3), orphan nuclear receptor‐α (ROR‐α), CD46, interferon regulatory factor 1 (IRF1), IRF4 and BAFF (Brockmann et al., 2017; Huang, Solouki, Koylass, Zheng, & August, 2017; Karwacz et al., 2017; Mascanfroni et al., 2015). All these stimulation factors make up a finely tuned network, and IL‐10 is the most important “master regulator” (Brockmann et al., 2017).

Tr1 cells also have peculiar immunosuppressive and anti‐inflammatory functions, including secreting inhibitory cytokines, cell contact inhibition, cytolysis, and metabolic disruption (Andolfi et al., 2012; Gregori & Roncarolo, 2018; Gregori et al., 2012; Roncarolo et al., 2014). In addition to IL‐10, Tr1 cells also can express high amounts of TGF‐β, variable amounts of IL‐5, granulocyte macrophage colony‐stimulating factor (GM‐CSF), and interferon‐γ (IFN‐γ), and minimal or no amount of IL‐2, IL‐4, and IL‐17 (Roncarolo et al., 2014; Zeng, Zhang, Jin, & Chen, 2015). Low or no expression of IL‐4 is an important identification point of Tr1 and Th2 cells. IL‐10 and TGF‐β are the most important suppressive cytokines of Tr1 cells (Zeng et al., 2015). Tr1 cells can express inhibitory receptors, including cytotoxic T lymphocyte antigen 4 (CTLA‐4), programmed death‐1 (PD‐1), and inducible costimulator (ICOS), which can exert an inhibitory effect on antigen‐presenting cells through cell–cell communication (Akdis et al., 2004). The secretion of Granzyme B and perforin also contributes to the suppressive capacity of Tr1 cells (Magnani et al., 2011). Furthermore, Tr1 cells can also inactivate extracellular ATP by extracellular enzymes such as CD39 and CD73, thereby preventing effector cell proliferation and cytokine production (Borsellino et al., 2007; Deaglio et al., 2007). The immunosuppressive and anti‐inflammatory effects of Tr1 cells are involved in multiple mechanisms. With the discovery of surface markers of Tr1 cells, many new mechanisms will be elucidated in the near future.

3. Tr1 CELLS IN AIDs

Selftolerance is a necessary condition to ensure the normal function of the immune system in the body. Peripheral selfantigen tolerance is mediated by multiple mechanisms and any damaged parts can lead to autoimmune attacks and diseases. Currently, both IL‐10 and Tr1 cells have been investigated in many AIDs in both laboratory and clinical studies. Because AIDs have a certain degree of similarity in the immunological and genetic levels during the pathogenesis of AIDs, the study results of IL‐10 and Tr1 cells in various AIDs are relatively consistent, that is, IL‐10 and Tr1 cells are often reduced in disease state and enhanced IL‐10 or IL‐10‐producing Tr1 cells has a tendency to relieve the disease. With the development of engineered Treg cells, Tr1 cells have gradually become a new focus of antigen‐specific cell immunotherapy. The studies on the changes of Tr1 cells in AIDs can provide novel ideas for developing novel and effective treatment strategies of AIDs. In the following sections, we will discuss how Tr1 cells affect several AIDs such as MS, IBD, RA, T1DM, and GD.

4. Tr1 CELLS IN MS

MS is a chronic AID in central nervous system mediated primarily by T lymphocytes with the specificity to neuronal antigens, characterized by inflammation, demyelination, and neurodegeneration (Hemmer, Kerschensteiner, & Korn, 2015). Immune system selfattacks distinguish MS from other neurological diseases, such as stroke and Alzheimer's disease (Hemmer et al., 2015; Karussis, 2014). MS often affects young people with genetic susceptibility and often cause disability (Waldman et al., 2014). The pathogenesis of MS has not been thoroughly explored yet, and currently, there are no drugs to completely control its progression (Karussis, 2014). Experimental autoimmune encephalomyelitis (EAE) is an important animal model for studying MS. IL‐10 has been proved to have a significant effect on preventing EAE (Dai, Ciric, Zhang, & Rostami, 2012; Klose et al., 2013; Kwilasz, Grace, Serbedzija, Maier, & Watkins, 2015). Previous studies have focused on other IL‐10‐producing cells, such as Th2 cells, however, with the discovery of Tr1 cell surface markers, more and more focuses are concentrated on Tr1 cells in patients with MS.

Many scientists have reported that the number of Tr1 cells is decreased in patients with MS or mouse models, and the function of Tr1 cells for secreting IL‐10 is also impaired. The underlying mechanisms have not been completely understood and the current findings mainly include the damage to CD46, impaired IL‐10 signal pathway, and decreased IL‐27. We have summarized the research progress of Tr1 cells in MS during the past decade, as shown in Table 1. CD46 is a type I membrane protein, and first identified as a member of the regulators from the complement activation family (Zaffran et al., 2001). Interestingly, CD46 is highly expressed at the blood–brain barrier in comparison to the liver and renal tissues (Shusta, Zhu, Boado, & Pardridge, 2002). Stimulating CD46 on T cells can trigger the transformation of Th cells into IL‐10 producing Tr1 cells (Kemper et al., 2003; Truscott et al., 2010), and then play an anti‐inflammatory effect. Astier et al. found that CD46 signal pathway is deficient in patients with MS and the altered regulation of the Cy2 (an intracytoplasmic tail of CD46) may be responsible for Tr1 cell defect in human MS (Astier & Hafler, 2007; Astier, Meiffren, Freeman, & Hafler, 2006). Choileain et al. found that T‐cell stimulation can alter the O‐glycosylation status of CD46, thus inducing the change of its mass, translocation to the immune synapse, and T‐cell activation. The cell surface abundance of CD46 is reduced upon the generation of Tr1 cells, thereby inducing the production of IL‐10. In contrast, T cells from patients with MS showed a reduced change in CD46 abundance and continued to produce the inflammatory cytokine IFN‐γ (Ni Choileain & Astier, 2011; Ni Choileain et al., 2017). IL‐10 is the most abundant cytokine secreted by Tr1 cells, and the presence of IL‐10 will, in turn, promote Tr1 cell differentiation and proliferation. IL‐10 reduction and signal pathway abnormality are the causes of decreased Tr1 number and inhibited functions in MS disease (Dai et al., 2012; Ma et al., 2009; Martinez‐Forero et al., 2008). In addition to IL‐10, IL‐27 as an important cytokine for stimulating Tr1 cells, its signal pathway abnormality has also been found in MS, and the number and function of Tr1 cells can be partially restored by exogenously increasing IL‐27 (Meka, Venkatesha, Dudics, Acharya, & Moudgil, 2015).

Table 1.

The discoveries about Tr1 cells of MS

References Samples Major discovery of Tr1 cells
Number Function Other discoveries
Zohar et al. (2018) Mouse model ↑After CXCL11‐Ig ↑After CXCL11‐Ig CXCL11 redirects the polarization of effector T cells into Tr1 cells and suppresses EAE in an IL‐10 dependent manner.
Ni Choileain et al. (2017); Ni Choileain & Astier (2011) Human blood ↓ ↓ Altered molecular mass and expression of CD46 are observed in T cells from patients with MS, thus inhibiting the secretion of IL‐10 by Tr1 cells.
Pennati et al. (2016) Mouse model ↑After Breg cell stimulation ↑After Breg cell stimulation Breg cells can improve MS by stimulating Tr1 cell expansion.
Meka et al. (2015) Human blood ↑After IL‐27 stimulation ↑After IL‐27 stimulation IL‐27 represents a novel and promising target/agent for the treatment of autoimmune diseases.
Apetoh et al. (2010) Mouse model ↑After AhR‐c‐Maf binding ↑After AhR‐c‐Maf binding AhR‐c‐Maf binding promotes the levels of IL‐10 and IL‐21, thus resulting in the generation of Tr1 cells and amelioration of experimental autoimmune encephalomyelitis.
Ma et al. (2009) Monkey model ↓ ↓ IL‐10 secretion impairment is specific to CD3/CD46 signaling but not to CD3/CD28.
Meiron et al. (2008) Mouse model ↑After CXCL12‐Ig ↑After CXCL12‐Ig CXCL12 functions as an anti‐inflammatory mediator that polarizes Tr1 cells in EAE
Astier et al. (2008); Astier & Hafler (2007); Astier et al. (2006) Human blood ↓ ↓ Tr1 cell defect in human MS is associated with CD46 signal pathway.
Martinez‐Forero et al. (2008) Monkey model ↓ ↓ The IL‐10 signaling is impaired, and the expression levels of STAT1, STAT3, and IL‐10RA genes are higher in patients with MS patients.
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Note. AhR: aryl hydrocarbon receptor; EAE: experimental autoimmune encephalomyelitis; IL: interleukin; MS: multiple sclerosis; Tr1: type 1 regulatory T cell.

In immune system splenic B cells and peritoneal B‐1a cells as well as Peyer's patch B cells can induce a particular subset of regulatory B (Breg or B10+) cells with many Treg cells associated features and immunosuppressive effects, such as the production of IL‐10 and the expression of CD25, CTLA‐4, PD‐1, and LAG3 (Lykken, Candando, & Tedder, 2015; Pennati et al., 2016). Breg cells can also secrete IL‐10 in a large amount, thereby promoting the differentiation and proliferation of Tr1 cells (Carter, Rosser, & Mauri, 2012; Pennati et al., 2016; Said, Barut, Mansur, Korkmaz, & Sayi‐Yazgan, 2018; Volchenkov et al., 2013). Pennati et al. (2016) found that exogenously elevated Breg cells in EAE mice can effectively increase the number and function of Tr1 cells and alleviate disease progression. Moreover, CXCL11, CXCL12, AhR, and c‐Maf are also stimulatory factors for Tr1 cells, because Tr1 cells can be restored and the disease can be alleviated by increasing these factors (Apetoh et al., 2010; Meiron, Zohar, Anunu, Wildbaum, & Karin, 2008; Zohar et al., 2018). In addition to mice, as early as a decade ago, scientists have studied Tr1 cells in monkey MS models with much closer human genes and immune environments to conclude that both the decreased number and function of Tr1 cells are associated with the impaired IL‐10 signal pathway (Ma et al., 2009; Martinez‐Forero et al., 2008)

4.1. Tr1 cells in other AIDs

In addition to MS, Tr1 cells have also been explored in many other AIDs, including RA, psoriasis, IBD, T1DM, GD, HT, and SLE. The recent studies are summarized in Table 2. In psoriasis disease, Kim et al. (2018) found that Tr1 cells are not only decreased in the disease state but also associated with disease severity, that is, the more serious disease can result in more difficulties in detecting Tr1 cells. Tr1 cells can be detected in normal skin of patients with psoriasis, but not in the lesion area. Similar results have also been found in GD and HT by Vitales‐Noyola et al. (2018). The number and function of Tr1 cells are correlated with disease conditions, such as the duration of disease, the activity of ophthalmopathy and autoantibody titers (Vitales‐Noyola et al., 2018). In patients with RA and animal models with collagen‐induced arthritis, scientists have also observed a decreased number of Tr1 cells and hypofunction. Nakachi et al. (2017) have found that the damage degree of Tr1 cells is related to the clinical activity index scores of the disease. Moreover, scientists have also found that Breg cells can correct the Tr1 cell‐related disorder, which is involved in IL‐10, as Pennati et al. (2016) found in MS (Carter et al., 2012; Mielle et al., 2018). Previous studies have conducted in blood and intestinal tissue samples from mice and humans with IBD (Alfen et al., 2018; Brockmann et al., 2017). The researchers have found that Tr1 cells play an immunosuppressive role through IL‐10 is related to p38 MAP kinase (Brockmann et al., 2017), and another important suppressive cytokine IFN‐γ secreted by Tr1 cells can inhibit the transfer of colitis (Alfen et al., 2018). As for T1DM, Yu et al. (2017) found that anti‐CD3 mAb in the animal model can result in the alteration of gut microbiota and the increase of Tr1 cells (Yu, Paiva, & Flavell, 2018). These intestinal antigen‐specific Tr1 cells can migrate to the periphery via CCR4, CCR5, and CCR7 and suppress the proliferation of Th1 cells in pancreatic tissue (Yu et al., 2017). Similarly, Chujo et al. (2015) found a decrease in the number of IGRP‐specific Tr1 cells in T1DM, especially in adult‐onset patients with T1DM. In SLE, Le Buanec et al. (2011) found that IFN‐α can stimulate nTreg differentiation into Tr1 in an inflammatory environment. In addition, Jin, Han, & Yu (2013) discovered that IL‐6‐induced IL‐10‐producing Tr1 cells can inhibit lipopolysaccharide (LPS)‐induced autoimmune inflammatory responses by constructing an multiorgan inflammation animal model. By summarizing previous studies, we found that the number and function of Tr1 cells are inhibited in AIDs, and the disease can be alleviated by correcting the abnormality of Tr1 cells.

Table 2.

The discoveries about Tr1 cells of other autoimmune diseases

References Diseases Samples Main discovery about Tr1
Number Function Other discoveries
Kim et al. (2018) Psoriasis Human blood and skin ↓ Unclear As the increase in the degree of inflammation, the proportion of Tr1 cells decreased, and Tr1 cells are not found in the skin lesion area.
Vitales‐Noyola et al. (2018) GD and HT Human blood and thyroid tissues ↓ ↓ Tr1 cell levels are associated with disease severity.
Mielle et al. (2018) RA Human blood ↑After Breg cell stimulation ↑After Breg cell stimulation Breg cells can increase the differentiation of naïve T cells into Treg cells and Tr1, through IL‐10 secretion and cellular communication
Nakachi et al. (2017) RA Human blood ↓ ↓ The damage degree of Tr1 cells is related to clinical disease activity index scores.
Carter et al. (2012) CIA Mouse model ↓ ↓ Similar with Tr1 cells, IL‐10‐producing B cells can restrain inflammation
Alfen et al. (2018) IBD Human intestinal tissue ↓ ↓ Tr1 cells can express IFN‐γ and efficiently suppress T‐cell proliferation and transfer colitis
Brockmann et al. (2017) IBD Mouse model and human blood ↓ ↓ IL‐10 can maintain IL‐10 production in Tr1 cells via the activation of p38 MAP kinase.
Yu et al. (2017) T1DM Mouse model ↑After anti‐CD3 mAb stimulation ↑After anti‐CD3 mAb stimulation Anti‐CD3 mAb can alter gut microbiota and increase Tr1 cells; these intestinal antigen‐specific Tr1 cells can migrate to the periphery via CCR4, CCR5, and CCR7 and suppress the proliferation of Th1 cells in pancreatic tissue.
Chujo et al. (2015) T1DM Human blood ↓ ↓ The frequency of IGRP‐specific Tr1 cells in adult‐onset T1DM patients is significantly lower than that in healthy adults and patients with juvenile‐onset T1DM.
Le Buanec et al. (2011) SLE Human blood ↑After IFN‐α stimulation ↑After IFN‐α stimulation IFN‐α can stimulate nTreg differentiation into Tr1 in an inflammatory environment.
Jin et al. (2013) Multiorgan inflammation Mouse model ↑After IL‐6 stimulation ↑After IL‐6 stimulation IL‐6‐induced IL‐10‐producing Tr1 cells can inhibit LPS‐induced autoimmune inflammatory responses.
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Note. CIA: collagen‐induced arthritis; GD: Greaves' disease; HT: Hashimoto's thyroiditis; IBD: inflammatory bowel disease; IGRP: islet‐specific glucose 6 phosphatase catalytic subunit‐related protein; IL: interleukin; RA: rheumatoid arthritis; LPS: lipopolysaccharide; SLE: systemic lupus erythematosus; T1DM: type 1 diabetes mellitus; Tr1: type 1 regulatory T cell.

5. THE THERAPEUTIC PROSPECT OF ENGINEERED Tr1

Reconstructing immune system by mediating Treg cells to treat AIDs is one of the current research hotspots. The adoptive transferring of FOXP3+ Treg cell therapy has been demonstrated in mouse models with multiple AIDs including SLE, T1DM, EAE, IBD, and CIA (Okamura et al., 2018). At present, antigen‐specific Treg cell therapy can ensure a certain degree of safety in the case of effective treatment, but there is still a risk of cross‐immunosuppression, which may be related to potential contamination of nonantigen‐specific Treg cells during the preparation (Stone et al., 2014). Although this method is currently focused on FOXP3+ Treg cells, scientists are constantly trying to use FOXP3− Tr1 cells for disease treatment. Recently, clinical trials using either FOXP3+ Treg or Tr1 cells have proven to be safe and have therapeutic efficacy (Gregori, Passerini, & Roncarolo, 2015). This strategy has been provided as a very useful clue and premise for later scientists to conduct Tr1 cell therapy. However, the proportion of Tr1 cells to monocytes in peripheral blood is very low. In vitro expanded Tr1 cells are also failed to fully determine whether their traits are well maintained after being introduced into the body. Moreover, the surface markers of Tr1 cells are still under continuous exploration, and the uncertainty of surface markers has brought the difficulties of Tr1 cell therapy. Although there are many difficulties in using Tr1 cells for disease treatment, the immunomodulatory function of Tr1 cells is still the interesting point of many scientists.

Several protocols have been established to produce human Ag‐specific Tr1 cells, including Tr1‐enriched cell lines, Tr1 cell clones, and Tr1‐like cell lines. In the Tr1‐enriched cell line protocol, donor‐derived peripheral blood mononuclear cell (PBMC) or CD4+ T cells are continuously stimulated for 10 days by host‐derived monocytes in the presence of IL‐10. Alternatively, PBMC or CD4+ T cells are cultured for 10 days with allogeneic dendritic cells (DCs), in the presence of recombinant human IL‐10 and GM‐CSF/IL‐4/IL‐10. To generate T‐allo10 cells, donor‐derived T cells are cultured with host‐derived DC‐10 and to induce host‐derived T10 cells, and T cells are stimulated with donor‐derived DC‐10 (Bacchetta et al., 2010; Mfarrej et al., 2017). In the protocol of Tr1 cell clones, PBMCs are stimulated with antigen (such as ovalbumin or collagen II) in the presence of IL‐2 and IL‐4 to enrich or amplify Ag‐specific T cells, followed by T‐cell cloning and amplification using Schneider (Brun, Bastian, Neveu, & Foussat, 2009; Brun et al., 2011). For Tr1‐like cell lines, human CD4+ T cells are preactivated with soluble anti‐CD3/CD28 mAb and IL‐2 for 48 hr and then transfected overnight with lentiviral vector (LV)‐IL‐10. The transfected T cells are isolated and expanded in the feeder mix. To generate allogeneic IL‐10‐transformed cells, naive CD4+ T cells are stimulated with allogeneic DCs and transfected with LV‐IL‐10 upon secondary stimulation. After selection, IL‐10‐transfected cells are expanded in vitro with the feeder mix (Andolfi et al., 2012; Locafaro et al., 2017).

Currently, Tr1 cell therapy is mainly studied in transplanted immune and hematological malignancies. Although Tr1 cells are most widely studied in AIDs, the studies on Tr1 cell therapy in AIDs are temporarily rare. At present, Tr1 cell therapy has been reported in clinical and preclinical trials for the treatment of myeloid leukemia and graft versus host disease (GVHD; Andolfi et al., 2012; Bacchetta et al., 2014; Locafaro et al., 2017; Mfarrej et al., 2017). Andolfi et al. (2012) constructed a Tr1‐like cell line and found that CD4 (LV‐IL‐10) T cells still have inhibitory functions in vivo and are effective in controlling GVHD, indicating that lentivirus‐transferred IL‐10 is stably expressed in human CD4+ T cells and can exhibit phenotype and function of Tr1 cells (Andolfi et al., 2012). Bacchetta et al. (2014) confirmed that Tr1 cell therapy is effective in patients with high‐risk or advanced hematologic malignancies treated with T‐cell haploidentical‐hematopoietic stem cell transplantation (haplo‐HSCT). Locafaro et al. (2017) found that LV‐IL‐10‐CD4 cells can prevent GVHD and promote graft versus leukemia effects in allogeneic HSCT in vitro and in vivo, in an HLA Class I‐dependent but antigen‐independent manner. Mfarrej et al. (2017) developed a drug rich in Tr1 cells by the protocol of Tr1‐enriched cell lines that is stable after cryopreservation. This drug allows circulating Tr1 cells to be minimally compromised in renal transplant recipients under standard immunosuppression and eventually starts to recover at 36 weeks posttransplantation, which provides the clues for determining the time of cell infusion (Mfarrej et al., 2017). Currently, there is no case of engineered Tr1 cell therapy that has been completed and published for the treatment of AIDs. Only one clinical study is underway to treat Crohn's disease by in vitro expanded ovalbumin‐specific Tr1 cells (http://www.txcell.com).

The current use of Tr1‐related therapies in AIDs is limited to the use of stimulants. Scientists have tried a variety of Tr1 cell stimulators including CXCL11, CXCL12, AhR‐c‐Maf, Breg cells, anti‐CD3 mAb, IFN‐α, and IL‐6, demonstrating that the disease can be alleviated after correcting the number and dysfunction of Tr1 cells (Table 3). CXCL11, CXCL12, and AhR‐c‐Maf are used to treat MS (Table 1), anti‐CD3 mAb is used in T1DM, and Breg cells is proven to be effective in both MS and RA. IFN‐α has been shown to promote nTreg to Tr1 differentiation in SLE. IL‐6 can increase the number and function of Tr1 cells in LPS‐induced autoimmune inflammatory responses.

Table 3.

The fundings in the therapeutic use of Tr1 cells in autoimmunity

Therapy Disease Sample Specific treatment After treatment References
Number of Tr1 Function of Tr1
Egineered Tr1 CD Patients In vitro expanded ovalbumin ‐specific Tr1 cells Unclear Unclear http://www.txcell.com
Tr1 stimulator MS Mouse model CXCL11 ↑ ↑ Zohar et al. (2018)
Mouse model Breg ↑ ↑ Pennati et al. (2016)
Human blood IL‐27 ↑ ↑ Meka et al. (2015)
Mouse model AhR‐c‐Maf ↑ ↑ Apetoh et al. (2010)
Mouse model CXCL12 ↑ ↑ Meiron et al. (2008)
RA Human blood Breg ↑ ↑ Mielle et al. (2018)
T1DM Mouse model anti‐CD3 mAb ↑ ↑ Yu et al. (2017)
SLE Human blood IFN‐α ↑ ↑ Le Buanec et al. (2011)
Multiorgan inflammation Mouse model IL‐6 ↑ ↑ Jin et al. (2013)
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Note. AhR: aryl hydrocarbon receptor; CD: Crohn's disease; IFN‐α: interferon‐α; IL: interleukin; Tr1: type 1 regulatory T cell; MS: multiple sclerosis; RA: rheumatoid arthritis; SLE: systemic lupus erythematosus; T1DM: type 1 diabetes mellitus.

The immunomodulatory effect of Tr1 cells can offer the potential for the development of therapeutic products, thus providing new ideas for inhibiting transplant rejection and treating AIDs. Complete clinical trials have demonstrated the safety and potential therapeutic efficacy of Tr1 cell therapy. Engineered Tr1 cells are currently available in vitro and protocols have been translated into clinical practice. However, mass production of antigen‐specific Tr1 cells in vitro still has certain risks, and the production process and storage conditions are not mature yet. Whether the antigen‐specific Tr1 cells have cross‐immunosuppression in vivo like FOXP3+ Treg cell therapy and the functional stability and safety of the engineered Tr1 cells in vivo remain to be further evaluated. Recently, scientists have discovered that Tr1 cells could express the transcription factor eomesodermin. Eomesodermin producing Tr1 cells are found in both human lymphoid and nonlymphoid tissues and are enriched in intestinal tissues. Eomesodermin has been found to play a lineage‐defining role in the differentiation of Tr1 cells and scientists believe that it has great therapeutic potential, but because it is highly dynamic in vivo, there are still few studies available (Gruarin et al., 2019; Zhang et al., 2017). Although there are still many unknowns in Tr1 cell‐related therapy, it is a research hotspot in the field of clinical immunology currently, and its public recognition will be definitely deepened in the near future. Therefore, the clinical application of Tr1 cell therapy will inevitably bring huge benefits to patients with AIDs.

6. CONCLUSION

Because the discovery of Tr1 cells nearly 20 years ago, studies have firmly confirmed its ability to secrete IL‐10 and immunosuppressive function. By summarizing a variety of AIDs, we found that Tr1 cells are often in a state of damage under disease conditions, manifested by decreased numbers and functional inhibition. Whether it is possible to restore immune system homeostasis and to treat AIDs by correcting abnormal Tr1 status is a direction worth studying. In terms of treatment, the preparation method of engineering Tr1 has been established and proven to be effective and has been shown to have therapeutic effects in various diseases, including myeloid leukemia, GVHD and Crohn's disease. Although Tr1 cells have many unknowns as a new hot spot in the immune community, we believe that Tr1 cells play an important role in AIDs and have enormous therapeutic potential. We hope that this study will provide useful information for later scientists to treat AIDs through Tr1 cell therapy.

CONFLICTS OF INTEREST

The authors declare that there are no conflicts of interest.

ACKNOWLEDGMENTS

The present work was supported by grants from the National Natural Science Foundation of China (No. 81670722 and 81471004). We thank all authors for participating in this study.

Contributor Information

Kaida Mu, Email: mukaida@163.com.

Jin‐an Zhang, Email: zhangjinan@hotmail.com.

References

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