Molecular switches for regulating the differentiation of inflammatory and IL-10-producing anti-inflammatory T-helper cells

Difeng Fang; Jinfang Zhu

doi:10.1007/s00018-019-03277-0

. 2019 Aug 20;77(2):289–303. doi: 10.1007/s00018-019-03277-0

Molecular switches for regulating the differentiation of inflammatory and IL-10-producing anti-inflammatory T-helper cells

Difeng Fang ^1,^✉, Jinfang Zhu ^1,^✉

PMCID: PMC11105075 PMID: 31432236

Abstract

CD4 T-helper (Th) cells secret a variety of inflammatory cytokines and play critical roles in host defense against invading foreign pathogens. On the other hand, uncontrolled inflammatory responses mediated by Th cells may result in tissue damage and inflammatory disorders including autoimmune and allergic diseases. Thus, the induction of anti-inflammatory cytokine expression becomes an important “brake” to repress and/or terminate aberrant and/or unnecessary immune responses. Interleukin-10 (IL-10) is one of the most important anti-inflammatory cytokines to limit inflammatory Th cells and immunopathology and to maintain tissue homeostasis. Many studies have indicated that Th cells can be a major source of IL-10 under specific conditions both in mouse and human and that extracellular signals and cell intrinsic molecular switches are required to turn on and off Il10 expression in different Th cells. In this review, we will highlight the recent findings that have enhanced our understanding on the mechanisms of IL-10 induction in distinct Th-cell subsets, including Th1, Th2, and Th17 cells, as well as the importance of these IL-10-producing anti-inflammatory Th cells in immunity and inflammation.

Keywords: T-cell activation, T-helper cell differentiation, Immunopathology, T-cell homeostasis, Transcriptional regulation, Cytokine expression, C-Maf, Bhlhe40

Introduction

In response to foreign- or self-antigens, naïve CD4 T cells differentiate into type 1 T helper (Th1), Th2, Th17, follicular T helper (Tfh), or peripherally derived T regulatory (pTreg) cells [1–3]. Master transcription factors (T-bet for Th1, GATA3 for Th2, and RORγt for Th17) control the fate determination of T-helper (Th) cells and the production of effector pro-inflammation cytokines [4, 5]. An appropriate immune response is critical for pathogen clearance; however, uncontrolled inflammatory responses, sometimes linked to a cytokine storm, can often result in severe immunopathology or chronic inflammation in the host. Regulatory cytokine IL-10, encoded by the Il10 gene, was originally named as cytokine synthesis inhibitory factor and it is mainly expressed by Th2 cells and inhibits Th1 cell differentiation [6]. As a multifunctional anti-inflammatory cytokine, IL-10 targets various innate and adaptive leukocytes to repress their activation and functions, through which it suppresses inflammatory cytokine eruption, prevents host damage, and maintains functional tissue integrity [7–9]. Up to date, many different cell types including CD4 T cells, CD8 T cells, dendritic cells (DCs), macrophages, mast cells, conventional natural killer cells (cNKs), eosinophils, neutrophils, B cells, as well as some innate lymphoid cells (ILCs) are reported to produce IL-10. Among the CD4 T cells, Foxp3⁺ Treg cells were thought to be the professional IL-10-producing CD4 T-cell subset [10, 11]. However, majority of the CD4⁺CD25⁺ Treg cells, except for intestinal Treg cells, do not produce IL-10 when they are immediately re-stimulated ex vivo [12], and retroviral transduction of Foxp3 fails to induce Il10 expression [13], suggesting that IL-10 production is not a unique feature of Treg cells. Nevertheless, IL-10 produced by Treg cells while not essential for controlling early onset of systemic autoimmunity, and it plays an important role in limiting immune responses in colon and lungs [14]. Foxp3-negative IL-10-producing CD4 T cells have been designated as Tr1 cells [15, 16]. However, in contrast to other effector Th-cell subsets, Tr1 cells do not have lineage-specific master transcription factor(s) to define their differentiation. Accumulating evidence shows that all Th-cell subsets, including Th1, Th2, and Th17 cells, have the capability to produce IL-10 both in vitro and in vivo [6, 17–19], and these Th cells may control their own inflammatory and anti-inflammatory functions through switching on and off IL-10 production. Thus, Tr1 cells may be very heterogeneous and they may not represent a separate lineage. Tr1 cells, by definition, include IL-10-producing cells from distinct effector Th-cell subsets. The molecular mechanisms of Il10 induction are still not fully understood partly due to its regulation being cell-type specific or environment dependent. In this review, we will summarize our knowledge on similarities and differences of molecular switches including important transcription factors for regulating Il10 expression in Th1, Th2, and Th17 cells, the presence of IL-10-producing Th-cell subsets in disease settings (both in human and in mouse), and their potential functions in regulating inflammatory and anti-inflammatory immune responses.

IL-10-producing Th cells in diseases

IL-10-producing Th2 cells in diseases

The function of IL-10-producing Th cells is brought into attention in both human and murine physiological and pathologic conditions (Fig. 1). IL-10 was first regarded as a Th2 cytokine. Indeed, peripheral blood mononuclear cells (PBMCs) from house dust mite (HDM)-sensitized asthmatic patients express both IL-5 and IL-10 after re-stimulated with antigen ex vivo [20]. In mouse skin, repeated infection with helminth Schistosoma mansoni larvae that elicits a strong Th2 response induces IL-10⁺ CD4 T-cell population which do not express Treg makers such as Foxp3, Helios, Nrp1, and CD223 [21]. Moreover, an in vitro proliferation assay shows that those IL-10⁺ CD4 T cells suppress the proliferation of CD4 T cells from the skin draining lymph nodes (dLNs). Furthermore, IL-4-producing Th2 cells are recognized as one of the major sources of IL-10 production during helminth infection [21] and in HDM-induced allergic airway inflammation [22]. In addition, IL-4- and IL-10-producing Th2 cells are important in tolerance during a successful pregnancy and in allograft, which has been reviewed by Chatterjee et al. [23].

IL-10-producing Th1 cells in diseases

IL-10 production by Th1 cells has also been reported in many disease settings. Malaria-specific IL-10⁺IFN-γ⁺ CD4 T cells are induced in children exposed to Plasmodium, although whether these co-producing CD4 T cells are associated with future protection is still controversial [24–26]. Nevertheless, it has been shown that IL-10⁺IFN-γ⁺ CD4 T cells are present in a higher frequency in uncomplicated malaria than that in severe malaria [26]. A recent review has summarized the role of IL-10 in malaria [27]. In another important human infectious disease leishmaniasis, IL-10-producing Th cells have been implicated in regulating pathogen clearance versus chronic infection. In cutaneous leishmaniasis patients, the major source of IL-10 is the CD25⁻CD127^−/lowFOXP3⁻ CD4 T cells, and the Il10 mRNA is correlated with IFN-γ, IL-27, and IL-21 [28]. During chronic Leishmania donovani infection, IL-10⁺IFN-γ⁺T-bet⁺ Th1 cells are dramatically expanded [29]. It is consistent with the observation that in a murine model of clinical isolated Leishmania major infection, IFN-γ⁺IL-10⁺Foxp3⁻ Th1 cells contribute to repressing the healing process [30]. IL-10 produced by T cell are also clinically relevant to tuberculosis pathogenesis [31–33]. Upon tubercle bacillus (TB) antigen- or anti-CD3 antibody-triggered stimulation, IL-10-producing CD4 T cells including Th1 (IL-10⁺IFN-γ⁺T-bet⁺), Th2 (IL-10⁺IL-4⁺GATA3⁺), Th17 (IL-10⁺IL-17⁺), and Treg cells (IL-10⁺CD4⁺CD25⁺Foxp3⁺) from PBMCs of the pulmonary tuberculosis (PTB) patients are expanded [34]. In addition, the frequency of IL-10⁺ Th1 cells and Treg cells is related to TB burden and disease severity [34]. Bronchoalveolar lavages (BAL) derived T-cell clones from TB patients produce significant IFN-γ and IL-10 [31]. A significant population of IL-10⁺T-bet⁺CD44^hi CD4 T cells are found 21 day post Mycobacterium tuberculosis (MTB) infection, and repress inflammatory Th1 cell function [35]. Such IL-10-producing Th1 cells may impair bacterial clearance and contribute to chronic infection [35]. IL-10⁺IFN-γ⁺ CD4 T cells are also observed in experimental murine models of acute respiratory syncytial virus (RSV) and Toxoplasma gondii (T. gondii) infection [36, 37]. The latter is a very useful model for investigating the dual functions of IL-10⁺ Th1 cells in pathogen clearance and in immunopathology, as deleting Il10 in T cells results in an enhanced control of parasite expansion but with severe immunopathology [37, 38].

IL-10-producing Th17 cells in diseases

Th17 cells can also express IL-10. The relationship between IL-10-producing Th17 cells and autoimmune diseases, including experimental autoimmune encephalomyelitis (EAE), type 1 diabetes (T1D), rheumatoid arthritis (RA), and inflammatory bowel disease (IBD), has been reviewed recently [39]. Clinically, higher Il10 mRNA in Th17 cells is found in clinically stable patients compared with patients with active multiple sclerosis (MS) [40]; myelin-reactive CD4 T-cell clones from healthy controls produce higher IL-10 compared to those from the MS patients that express higher levels of IFN-γ, IL-17, and GM-CSF [41]. These observations suggest that IL-10-producing Th17 cells may be beneficial in controlling autoimmunity and that these cells are either repressed or switched to the IL-10⁻ Th17 cells in the MS patients. In addition, during the acute dry eye disease (DED), reduced frequency of IL-10⁺ Th17 cells is associated with an increased production of IL-17 and IL-23 and a higher frequency of IL-17⁺ CD4 T cells [42], suggesting that the IL-10-producing Th17 cells are important to repress the inflammatory Th17 cells. IL-10-producing Th17 cells are also found during pathogen infection. For example, Staphylococcus aureus-primed human naïve CD4 T cells will differentiate into IL-10-producing Th17 cells [43]. In Neuroadapted sindbis virus (NSV) infection murine model, Il10^−/− Th17 cells in the CNS have Th1/Th17 phenotype and seem to be more pathogenic [44, 45].

Genomic organization of the Il10 locus in T cells

The Il10 locus includes 5 exons, and several DNase I hypersensitivity sites (DHSs) that have been identified in different immune cells [19, 46] (Fig. 2). DHSs are functionally related to transcriptional activity and necessary for the binding of many transcription factors. While naive CD4 T cells lack DHSs at the Il10 locus, Th1 and Th2 cells display different inducible DHSs at the Il10 locus, indicating that Th1 and Th2 cells utilize different mechanisms to induce Il10 expression [46–48].

Il10 locus in Th2 cells

Four important DHSs are found at the Il10 locus in different Th cells: DHS-9, DHS-transcriptional start site (DHS-TSS), DHS + 3, and DHS + 6.5 (Fig. 2). Distinct from Il10 regulation in Th1 cells, the Il10 locus in Th2 cells seems to be fully prepared to produce IL-10, since no additional DHS is induced upon reactivation when higher levels of Il10 mRNA are induced in differentiated Th2 cells [47]. In Th2 cells, DHS + 6.5 (6.5 kb downstream of the TSS), conserved between murine and human, is a strong DHS and bound by c-Jun and JunB; however, this site is not bound by c-Jun and JunB in Th1 cells [49]. More importantly, DHS + 6.5, but not the Il10 promoter, responds to phorbol myristate acetate (PMA) and ionomycin stimulation [49]. In addition, E4BP4, IRF4, c-Jun, JunB, and Etv5 bind to the DHS + 6.5 region rather than the Il10 promoter to induce IL-10 expression in Th2 cells [50]. The master transcription factor (TF) of Th2 cells, GATA3, binds to DHS-TSS [51, 52] and DHS-3.7 [51] in addition to DHS + 6.5 [50]. These data suggest that DHS + 6.5 is the major Il10 trans-activity site, at least in Th2 cells. Similarly, DHS-9 bound by NFAT1 and IRF4 is critical for Il10 induction in Th2 cells, not Th1 cells [53]. Even for the transcription factor c-Maf, which was initially reported to regulate IL-10 production in macrophages [54, 55] and seems to be a common Il10 inducer in different cell types [56, 57], its binding patterns in different Th-cell subsets are lineage-specific.

Il10 locus in Th1 and Th17 cells

STAT4, Blimp-1, and c-Maf co-bind to DHS-9 in Th1 cells; however, the binding of c-Maf is independent of Blimp-1 [58]. Recent studies also show that Th1 cell master TF T-bet and Bhlhe40 co-bind to DHS-9 and DHS + 6.5 [59, 60], but DHS + 3 is only bound by T-bet [59]. TGF-β downstream molecular Smad4 also binds to the Il10 promoter in Th1 cells [61, 62]. In Th17 cells, JunD, IRF4, BATF, and STAT3 bind to DHS + 3 and DHS-9 [63]. Th17 cell master TF RORγt and Trim33 co-bind to DHS-9 [64]. Canonical Notch signaling molecule RBPJ may bind to the Il10 promoter and repress c-Maf-mediated Il10 expression, although the binding of RBPJ to the Il10 is weak [65].

Shared molecular switches of inflammatory and IL-10 producing anti-inflammatory Th cells

IL-27 is a potent Il10 inducer

As mentioned above, different Th-cell subsets may utilize distinguished mechanisms to regulate Il10 expression, but they also share several similar signaling pathways (Fig. 3). IL-27 is a powerful cytokine for Il10 induction in all Th cells. IL-27 is initially reported to promote Th1-cell polarization together with IL-12 [66]. Later studies suggest that IL-27 may also exert anti-inflammatory function [67, 68]. Indeed, IL-27 could induce c-Maf, IL-21, IL-21R, and ICOS expression in CD4 T cells [69]. c-Maf is an important transcription factor for inducing IL-10 expression both in mice and in humans [70, 71]; IL-21, which can be produced by Th1, Th2, and Th17 cells, has been reported to promote Th1 and Th17 cells, but not Th2 cells to produce IL-10 in vitro [72]; in steady state, ICOS^high CD4 cell population in the secondary lymphoid organs is highly correlated with IL-10 production [73]. Under the in vitro Th1 cell-polarizing condition, IL-27 promotes IFN-γ⁺IL-10⁺ Th1 cell population, but has no effect on IFN-γ production; in Th2 cell-culture condition, IL-27 increases IL-10 production, but reduces IL-13 expression. IL-27 together with TGF-β enhances IL-10 expression and inhibits Foxp3 expression [74]. IL-27 and TGF-β also increase IFN-γ⁺IL-10⁺ cells in vitro neutral condition [75]. Furthermore, Il27ra^−/− mice infected with T. gondii fail to produce IL-10⁺ CD4 T cells [74]. In vitro neutral condition, IL-27-induced Il10 expression depends on STAT1 and STAT3, but not STAT4 [74, 76]. From the PBMCs of PTB patients, IL-27 expands the IL-10⁺ Th1, Th17, and Treg cell population, and TGF-β promotes the expansion of IL-10⁺ Th2, Th17, and Treg cell population [34].

Fig. 3 — Regulators of IL-10 expression in T-helper cells. IL-10-producing Th cells can be induced and regulated through different mechanisms which include: extracellular physical and chemical factors; cytokine and membrane proteins that trigger signaling; cytoplasmic signaling regulators; transcription factors in the nucleus. Th cells may share some common mechanism and regulators to induce IL-10 expression, such as PKCθ, c-Maf, Bhlhe40, etc. However, each Th-cell subset also has its own lineage-specific regulators for switching on and off IL-10 production

Other common Il10 regulators

Many signaling molecules have been identified to regulate Il10 expression in all Th cells. For example, ERK1 and ERK2 activation are required for IL-10 production by Th1, Th2, and Th17 cells [77]. Serine/threonine kinase glycogen synthase kinase-3 (GSK3) inhibitor does not affect Il10 expression in recently activated T cells; however, it dramatically up-regulates IL-10 and c-Maf production and regulates histone H3 acetylation and methylation in long-term re-stimulated Th1, Th2, and Th17 cells in vitro [78]. From experiments using Tg4 T-cell receptor transgenic mice, protein kinase C theta (PKCθ) has been shown as an essential regulator in myelin basic protein (MBP) Ac1-9[4Y] antigen-induced IL-10⁺ CD4 T cells [79]. Since c-Maf is down-regulated in PKCθ-deficient cells and c-Maf is a major inducer of Il10 expression in a variety of cells [19, 80], the effect of PKCθ in Il10 induction may be through c-Maf upregulation.

Although many factors and pathways are common in different Th-cell subsets in regulating IL-10 production, there are also Th-cell subset-specific mechanisms of Il10 induction; such mechanisms involve TFs and extracellular cytokines, as well as cell-surface proteins, intracellular kinases, and metabolism-related molecules (Fig. 3). Below, we will discuss molecular switches for IL-10 regulation in each Th-cell subset.

Switches of inflammatory and IL-10-producing anti-inflammatory Th2 cells

IL-10 production has been considered as a natural capability of Th2 cells [6, 81]. Il10 expression is down-regulated in Gata3-knockdown Th2 clones using an antisense Gata3 construct, but up-regulated in CD4-Gata3 transgenic Th1 cells [81]. GATA3 binds to the Il10 promoter region, and ectopic expression of GATA3 promotes histone acetylation at the Il10 locus; however, reporter assay indicates that GATA3 does not enhance the transcription activity of the Il10 promoter [51]. Therefore, the main function of GATA3 is possibly to make the Il10 locus more accessible in Th2 cells. It has been reported that the binding of GATA3 to the Il10 promoter is higher in IL-10⁺ Th2 cells than in IL-10⁻ Th2 cells [52]. Th2 cytokines are also shown to regulate Il10 expression. In vitro and ex vivo experiments suggest that repeated IL-4 treatment is essential for Th2 cells to express high levels of IL-10 [52]. IL-4-signaling engagement induces IL-10 production under the Th1 cell-culture conditions without affecting the expression of IFN-γ and T-bet [82]; similarly, IL-13 increases IL-10 production but only in polarized Th17 cells [83]. Since IL-4-mediated STAT6 activation is also responsible for GATA3 upregulation, whether STAT6 directly or indirectly induce Il10 expression needs further investigation. Interestingly, it has been recently reported that inflammatory cytokine IL-1 promotes IL-13 production, but inhibits IL-4 and IL-10 production by Th2 cells [84].

Transcription factors E4BP4, GATA3, IRF4, c-Jun, JunB, and Etv5 can bind to the Il10 locus at the DHS + 6.5 region rather than the promoter to induce Il10 expression in Th2 cells [50]. E4BP4, encoded by Nfil3, is essential for IL-10 production in both Th1 and Th2 cells by regulating histone modifications at the Il10 locus [85]. Etv5 also regulates IL-10 production in Th1 and Th2 cells, but it doesn’t affect IFN-γ and IL-4 production. Etv5 does not regulate the expression of Nfil3, Gata3, Irf4, Jun, and Junb, suggesting that its effect on Il10 expression is independent of regulating the other known IL-10 regulators [50]. NFAT1 directly binds to the Il10 locus at the DHS-9 region in Th2 cells, but not in Th1 cells, and NFAT1 is essential for IL-10 production in Th2 cells upon stimulation of PMA/ionomycin [53]. Furthermore, Ikaros (IKZF1) has been reported to positively regulate IL-10 production in Th2 cells and IKZF1 strongly binds to DHS-TSS region of the Il10 gene [86].

Self-regulation of IL-10-producing Th2 cells

Under in vitro Th2 cell-culture conditions, higher percentage of IL-4, IL-5, and IL-13-producing CD4 T cells can be generated from Il10ra^−/− CD4 T cells than from wild-type CD4 T cells, and in vivo, more IL-4, IL-5 and IL-13-producing CD4 T cells are detected in the lung and mediastinal LN of HDM-immunized Il10ra^−/− mice compared to wild-type mice [22]. These results suggest that IL-10 may directly act on T cells to inhibit Th2-cell differentiation and function; however, whether all Th2 cells express IL-10R and whether IL-10R expression is related to IL-10 production in Th2 cells are unknown. An early study also shows that IL-10 treatment together with allergen re-challenge through intratracheal inhibits IL-4 and IL-5 secretion in the bronchoalveolar lavage [87]. However, another study indicates that IL-10 produced by DC and T cells is important for CD4 T cells to produce IL-4 and IL-10 inhibits IFN-γ production in tape stripping-mediated allergic dermatitis [88]. IL-10 produced by Th2 cells could either repress IL-10R⁺ non-Th2 cells to boost a Th2 response or inhibit IL-10R⁺ Th2 cells to dampen a Th2 response. Considering the “natural” IL-10-producing capability of Th2 cells, regulating IL-10R expression on Th2 cells may be a critical self-regulatory mechanism.

Switches of inflammatory and IL-10-producing anti-inflammatory Th1 cells

Cytokines that regulate IL-10-producing Th1 cells

A strong Th1 response is essential for pathogen clearance; however, uncontrolled production of Th1 effector cytokine IFN-γ may lead to severe tissue damage and sometimes death of the host due to severe immunopathology [19, 89–91]. The space–time-dependent balance between IFN-γ⁺ and IL-10⁺IFN-γ⁺ Th1 cells is essential for an effective immune response with limited tissue damage. An important anti-inflammatory function of IL-10⁺IFN-γ⁺ Th1 cell has been highlighted in the T. gondii infection-induced type 1 immune response. Il10^−/− mice suffer from cytokine storm-mediated immunopathology and ultimate death, although the parasite is effectively controlled [92]. Several switches in controlling the balance between IFN-γ⁺ and IL-10⁺IFN-γ⁺ Th1 cells have been reported. In the Plasmodium chabaudi infection-induced malaria murine model, Il27ra^−/− mice failed to generate the IL-10⁺IFN-γ⁺ CD4 T-cell population [93]. During the course of blood-stage malaria infection, IFN-γ⁺ CD4 T cells are the major source of IL-10 both in the liver and lung, and IL-10 expression is controlled by IL-27R-mediated signaling in CD4 T cells [94]. Thus, IL-27 signaling plays a critical role in IL-10⁺ Th1-cell induction in vivo. A strong and long-lasting IL-12-STAT4 signaling, which is essential for T-bet expression and Th1-cell differentiation, together with high-dose TCR engagement can induce the development of IL-10-producing Th1 cells both in vitro and in vivo [77]. Results from both in vitro and ex vivo experiments indicate that repeated IL-12 exposure is able to induce Th1 cells to express high levels of IL-10 [52]. Interestingly, in the T. gondii STAg-immunized genetically resistant BALB/c and susceptible C57BL/6 mice, IL-10 expression by IFN-γ⁺ Th1 cells is independent of IL-12 [95], which suggests that IL-12 signaling is sufficient but not necessary for Th1 producing IL-10. Interestingly, although TGF-β inhibits Th1-cell differentiation through repressing T-bet and IFN-γ, it promotes antigen-specific effector Th1 cells to express IL-10 and up-regulates IFN-γ without affecting T-bet expression [62, 96]. Under in vitro Th1 or Th2 cell-culture conditions, either retrovirus-mediated TGF-β1 over-expression or addition of recombinant TGF-β1 promotes IL-10 production [61]. Under un-skewing cell-culture conditions, TGF-β could further promote IL-27-mediated IL-10 production independent of Blimp-1 [58]. TGF-β1 also causes Smad4 binding to the Il10 promoter and promotes Il10 transcription in Th1 cells [61, 62]. However, TGF-β has also been reported to inhibit Il10 expression in Th1 cells and to suppress Blimp-1 expression both in Th1 and Th17 cells [58, 97]. Altogether, it is possible that TGF-β could stabilize IL-10⁺IFN-γ⁺ cell population and that the functions of TGF-β in regulating Il10 expression are cell content dependent. By contrast, IL-1 family members including IL-1β and IL-18 suppress IL-10 production in Th1 cells [98].

Transcription factors that regulate IL-10-producing Th1 cells

Recently, several studies have demonstrated that the transcription factor Bhlhe40 represses IL-10 production in Th1 cells during Mycobacterium tuberculosis (MTB) or T. gondii infection, or in Th17 cells during EAE disease induction [59, 60, 99]. Yu et al. show that Bhlhe40 inhibits IL-10 expression, but promotes IFN-γ production without affecting T-bet expression [99]. Bhlhe40^−/− mice with increased IL-10 production fail to control parasites; on the other hand, Bhlhe40 deficiency results in loss of the pathogenicity of CD4 T cell in inducing colitis [99]. Huynh et al. show that CD4 T cells and other immune cells including dendritic cells require Bhlhe40 to repress Il10 expression during MTB infection [60]. Lin et al. also reported that Bhlhe40 deficiency results in increased IL-10 production in Th1 and Th17 cells [59]. Although Bhlhe40^−/− Th2 cells have normal IL-10 production in this study [59], Yu et al. have reported that Bhlhe40 also regulates IL-10 production in Th2 cells [99]. Bhlhe40 directly binds to several sites at the Il10 locus [59]. Interestingly, Bhlhe40 binds to the DHS + 6.5 site, where c-Maf binds in Th1 cells [60, 100]. Furthermore, in Bhlhe40^−/− Th1 cells, the expression of c-Maf and an Ikaros family member IKZF3 is up-regulated [99]. IKZF3 has also been shown to induce IL-10 production in Th17 cells [101]. Thus, Bhlhe40 may repress Il10 induction directly through its binding to the Il10 gene or indirectly through inhibiting the expression of two IL-10 inducers, c-Maf and IKZF3.

Another important TF involved in inducing IL-10⁺ Th1 cells is Blimp-1 [58]. However, Blimp-1 is not induced in Th2 or Th17 cells and thus is dispensable for IL-10 expression in these cells. Together with the IL-12-STAT4 signaling, Blimp-1 promotes IL-10 production in Th1 cells both in vitro and in vivo with T. gondii infection [58]. Interestingly, Blimp-1, STAT4, and c-Maf co-bind to the DHS-9 region of the Il10 locus, although STAT4 but not Blimp-1 regulates histone modifications at the DHS-9 region [58]. During chronic LCMV infection, Blimp-1 is required for viral-specific Th1 cells to produce IL-10 accompanied by reduced inflammatory function of these cells, and such function of Blimp-1 seems to be independent of the expression of c-Maf, AhR, NFIL3, or RBPJκ [102]. Single-cell RNA-Seq analysis performed on the antigen-specific IL-10-producing cells shows that Prdm1 (encoding Blimp-1) and Maf are co-expressed in the IL-10-expressing CD4 T cells [103]. Low levels of c-Maf expression are detected in Th1 cells, and c-Maf binding to the DHS-9 site is independent of Blimp-1 in Th1 cells [58]. In addition, IL-27-mediated induction of IL-10 and Blimp-1 depends on another transcription factor early growth response gene 2 (Egr2), whose induction depends on IL-27-mediated STAT3 activation. Luciferase reporter assay indicates that direct binding of Egr2 to the Prdm1 promoter trans-activates the expression of Prdm1 [104]. E4BP4 and Etv5, which regulate IL-10 production in Th2 cells as mentioned above, may also regulate Il10 expression in Th1 cells [50, 85].

Surface and intracellular molecules that regulate IL-10-producing Th1 cells

Besides cytokine-mediated signaling, other cell-surface protein-triggered signaling such as Notch pathway may enhance IL-10 production in Th1 cells [58, 105]. Dll4 stimulation enhances the binding of c-Maf to the DHS-9 region, and constitutively active form of Notch can no longer induce IL-10 production in Th1 cells in the absence of Blimp-1 [58]. Therefore, Notch-mediated induction of Il10 expression in Th1 cells requires both Blimp-1 and c-Maf. Moreover, when high levels of IL-2 are present, complement regulator CD46 may convert IFN-γ⁺ Th1 cells into IL-10⁺IFN-γ⁺ Th1 cells [106]. ERK and/or JNK signaling may be involved in CD46-mediated induction of IL-10⁺ Th1 cells [89]. In human CD4 T cells, knocking-down the expression of the cell-surface protein T-cell Ig and ITIM domain (TIGIT), which binds to DC surface protein CD155, results in increased T-bet and IFN-γ expression, but reduced Il10 expression, indicating that TIGIT plays a positive role in IL-10 induction [107].

Some intracellular molecules that are involved in the induction of IL-10⁺ Th1 cells have been summarized by Cope et al. [89]. For example, Src family kinase Lck is known to regulate Th2-cell differentiation. However, Lck^−/− Th1 cells express higher levels of IL-10 and c-Maf, but normal levels of IFN-γ and T-bet compared to wild-type Th1 cells [108]. Recently, the cholesterol biosynthesis pathway but not the cellular cholesterol content has been found to regulate IL-10 production in IFN-γ⁺ and TNF-α⁺ human Th1 cells, but not in Th17 cells [109]. Physiological level of 25-hydroxycholesterol is sufficient to repress c-Maf expression [109]. It has also been reported that cord-blood-derived mesenchymal stromal cells (MSCs) display immune regulatory properties in autoimmune disease, and induce IFN-γ⁺ IL-10⁺ Th1-cell population [110, 111].

No self-regulation of IL-10-producing Th1 cells

Since only a small population of Th1 cells express IL-10R, and IL-10⁺IFN-γ⁺ Th1 cells do not repress T-bet and IFN-γ expression by other Th1 cells [62], it is unlikely that IL-10 produced by anti-inflammatory IL-10⁺IFN-γ⁺ Th1 cells directly acts on inflammatory IFN-γ⁺ Th1 cells. It has also been noticed that IFN-γ-producing capability is similar between IL-10⁻ Th1 and IL-10⁺ Th1 cells isolated from T. gondii-infected mice. When co-cultured with T. gondii-infected macrophages, IL-10⁺ Th1 cells significantly suppress IL-12 production by these macrophages and this suppressive effect is reversed by the addition of the IL-10R-neutralizing antibody [37]. Therefore, it is possible that IL-10⁺IFN-γ⁺ Th1 cells attenuate pro-inflammatory cytokine production and thus pro-inflammatory Th1 response through repressing antigen presenting cells (APCs). Another interesting observation is that ex vivo IL-10⁻ Th1 cells can express IL-10 when they are re-activated with anti-CD3 antibodies, and IL-10⁺ Th1 cells will lose IL-10 production when resting in culture [37]. Thus, different from the IL-10-producing Th2 cells, IL-10⁺IFN-γ⁺ Th1 cells may represent a transient stage of Th1 cells.

Switches of inflammatory and IL-10-producing anti-inflammatory Th17 cells

Cytokines that regulate IL-10-producing Th17 cells

Th17 cells are best known as pro-inflammatory effector cells in many autoimmune diseases and during certain pathogen infection [112]. Recently, IL-10-producing anti-inflammatory Th17 cells have been reported, especially in the protection barrier of the intestine. Although IL-10 is difficult to be detected in human Th17 cells ex vivo after PMA/ionomycin treatment, TCR-stimulated human Th17 cell clones can produce IL-10, and both IL-10⁺IL-17A⁺ and IL-10⁺IFN-γ⁺ CD4 T cells are found in mouse small intestine [40, 113]. TGF-β1 and IL-6 can induce non-pathogenic Th17 cells that do not induce EAE in a transfer model, and these Th17 cells express high levels of anti-inflammatory cytokine IL-10 and c-Maf, but lower levels of chemokine gene Ccl5, Cxcl10, Ccl2, Cxcl2, and Ccl22 expression. By contrast, IL-23 induces inflammatory Th17 cells, which express high levels of pathogenic signature genes Il23r, Sgk1, Ccl4, Gzmb, Lrmp, Grp65, Plzp, Toso, and Lag3 [114, 115]. IL-6 cooperates with TGF-β to promote IL-10 and c-Maf expression in vitro and c-Maf induces IL-10 production during Th17 cell differentiation [116]. However, it has also been reported that IL-6 induces naïve CD4 T cells to produce IL-10 independent of IL-27 and TGF-β [117]. In the absence of TGF-β1, IL-23 may induce pathogenic Th17 cells that do not express IL-10 [118]. Interestingly, IL-23 induces the expression of TGF-β3 which together with IL-6 preferentially induces pathogenic Th17 cells by down-regulating the expression of IL-10 and its inducer c-Maf and AhR; all these molecules are up-regulated by TGF-β1 in the presence of IL-6 [11, 115, 119, 120]. Interestingly, IL-10⁺ Th17 cells express high levels of IL-27R in the peritoneal fluid of endometriosis patients compared to healthy controls. WSX-1 (an IL-27R subunit)-expressing Th17 cells in peritoneal fluid from endometriosis mice express higher levels of IL-10, Blimp1, and c-Maf, but low levels of RORγt compared to the WSX-1⁻ Th17 cells [121]. These results indicate a critical role of IL-27 signaling in the induction of Il10 expression in both humans and mice. Thus, TGF-β1, together with IL-27, may educate inflammatory Th17 cells to become anti-inflammatory Th17 cells. Other cytokines are also involved in regulating Il10 induction in Th17 cells. For example, Type I IFNs including IFN-β repress IL-17 and RORγt, but induce IL-10 expression under Th17 cell-polarizing culture conditions; however, whether IFN-β regulates IL-10⁺IL-17⁺ co-producing Th17 cells or inhibits Th17 cell differentiation to Th2 cell phenotype still needs further investigation [122–124]. On the other hand, IL-1β inhibits IL-10 production in S. aureus-primed Th17 cells [43] similar to the function of IL-1β in regulating IL-10 production in Th2 cells as mentioned previously [84]. Interestingly, IL-1β has been reported to induce the expression of Bhlhe40 in Th17 cells, which is known to suppress IL-10 [59, 125]. Furthermore, blocking another inflammatory cytokine TNFα induces IL-10 production in Th17 cells through up-regulating IKZF3 [101].

Transcription factors that regulate IL-10-producing Th17 cells

Transcription factor RORγt and tripartite motif-containing 33 (Trim33), which regulates TGF-β/Smad-signaling pathway [126], are required for Th17-cell differentiation both in vivo and in vitro, and both repress IL-10 production [64]. Trim33 and RORγt co-bind to several sites at the Il17a and Il10 locus, including the DHS-9 region at the Il10 locus, and regulate histone modifications at these regions [64, 127]. It has been reported that in Th17 cells, c-Maf directly binds to and trans-activates the Il10 promoter [116]. However, c-Maf expression is not altered in Trim33^−/− Th17 cells [64]. This suggests that Trim33 may directly repress Il10 expression. Canonical Notch signaling downstream molecule RBPJ binds to the Il23r and Il10 promoter [65]. While RBPJ promotes Il23r expression, it represses c-Maf-mediated Il10 induction. Therefore, RBPJ may facilitate the differentiation of inflammatory Th17 cells through both inhibiting Il10 induction and promoting IL-23 signaling.

Cellular homeostasis and IL-10-producing Th17 cells

Intracellular protein CD5L binds to cytosolic fatty acid synthase and regulates lipid metabolism [128]. CD5L deficiency does not affect Th17 cell differentiation; normal expression of Th17 signature genes Il17f, Il21, Il23r, Rorc, and Rora, but reduced expression of Il10 and Maf is found in Cd5l^−/− Th17 cells [129]. RORγt binding to the Il10 DHS-9 is reduced in Cd5l^−/− Th17 cells, and the ratio of polyunsaturated fatty acid (PUFA) and saturated (SFA) correlates with the RORγt binding to the Il10 DHS-9 [129], although the importance of such binding in regulating Il10 expression is still unknown. Anyway, this study indicates that intracellular fatty acid composition is involved in regulating the differentiation of IL-10-producing anti-inflammatory Th17 cells. One of the heme oxidation products, unconjugated bilirubin (UCB), is also reported to favor the differentiation of IL-10⁺IL-17⁺ anti-inflammatory Th17 cells in the dextran sulfate sodium (DSS)-induced colitis model. In the presence of UCB, CD4 T cells from PBMCs of healthy individuals are more likely to differentiate into IL-10-producing Th17 cells when polarized in vitro in presence of IL-6, IL-1β, and TGF-β [130]. Taken together, metabolism pathways may play important roles in the differentiation of IL-10-producing Th17 cells.

A critical factor for a successful pregnancy is the immune tolerance to the fetus. Interestingly, patients with multiple sclerosis suffer a reduced clinical symptom during their pregnancy [131], suggesting that pregnancy may induce anti-inflammatory cells. It has been reported that estrogen may reduce EAE symptoms through G-protein-coupled estrogen receptor (GPER) [132]. Under Th17 cell-culture conditions in vitro, GPER small molecule agonist G-1 up-regulates IL-10 production in Th17 cells [133]. Furthermore, glucocorticoid dexamethasone induces human memory CD4 T cells to co-express IL-17 and IL-10 or IFN-γ and IL-10 [134]. Hypoxia condition (1% O₂) is reported to significantly induce Il10 expression in Th17 cells compared with normal 21% O₂ [135]. High salt (NaCl) diet potentiates inflammatory Th17 cell differentiation and enhance EAE induction through serine/threonine kinase serum glucocorticoid kinase 1 (SGK1) and by up-regulating IL-23R expression [136]. All above findings suggest that the balance between inflammatory and anti-inflammatory Th17 cells is quite sensitive to environment changes and subsequent alterations in regulatory host factors.

Self-regulation of IL-10-producing Th17 cells

Th17 cells express high levels of IL-10Rα, and IL-10 inhibits IL-17A⁺IFN-γ⁺ and IL-17A⁺IFN-γ⁻, but not IL-17A⁻IFN-γ⁺ cell population in the T-cell transfer colitis model [113]. This indicates that IL-10 can directly repress IL-10R⁺ Th17 cells, although IL-10R expression by Treg cells is also essential for inhibiting Th17-mediated inflammation in the colitis model [137]. Th17 cells may also lose IL-10 production during long-term activation [40, 41]. Interestingly, strong TCR/CD28 stimulation not only suppresses human Th17-cell differentiation, but also represses c-Maf expression in Th17 cells [138].

IL-10-producing innate lymphoid cells (ILCs)

ILCs are considered as the innate counterparts of CD4 T-helper cells [4, 139]. Interestingly, just as T-helper cells, ILCs can be classified into at least three different groups: group 1 ILC (ILC1), group 2 ILC (ILC2), and group 3 ILC (ILC3) that resemble Th1, Th2, and Th17 cells, respectively. Compared to numerous studies on IL-10 regulation in Th cells, there are relatively fewer studies on IL-10 production by ILCs. In 2009, Prf1^−/− NK cells were found to express IL-10 [140]. In 2010, a Lin⁻IL-13⁺T1/ST2⁺IL-17BR⁺ cell population (now known as ILC2s) were identified and they have capability to produce IL-10 upon IL-25/IL-33 treatment or helminth infection [141]. However, in 2016, single-cell transcriptomic analysis on small intestinal ILCs did not classify the IL-10-producing cell subset [142]. In 2017, Wang et al. identified a Lin⁻CD45⁺CD127⁺IL-10⁺ ILCs population in small intestine, and TGF-β is required for their expansion [143]. No IL-10-producing ILCs are present in the lung of naïve mice, but upon IL-33 and papain treatment, Lin⁻CD45⁺Thy-1.2⁺ST2⁺IL-10⁺ ILC2s are induced [144]. Because of limited reports on IL-10 induction in ILCs, it is not clear whether the regulation and production of IL-10 in ILCs shares similar mechanisms that are found in Th cells. Further studies on the identification of IL-10-producing ILC subsets both in humans and mice under physiological and pathological conditions, and on the molecules and DNA elements that regulate IL-10 production in ILCs are required to expand our knowledge on the regulation of inflammatory and anti-inflammatory ILCs.

Conclusions

A well-balanced immune response, involving both inflammatory and anti-inflammatory lymphocytes, is critical for providing effective host protection against pathogen invasion and for preventing chronic inflammatory diseases. IL-10 is a well-studied member of an important anti-inflammatory cytokine family [91]. Although IL-10 can be expressed by many cell types, lymphocytes are a major source of IL-10 production. Besides regulatory T cells, all the effector CD4 T cells are capable of expressing IL-10. IL-10-producing cells are very heterogeneous and contain subsets that are derived from distinct effector CD4 T cells. Even within the IL-10-producing Th1 cells, it has been recently shown that only the IL-10-producing cells co-expressing co-inhibitory receptors are anti-inflammatory, whereas the IL-10-producing cells that do not express co-inhibitory receptors are actually inflammatory, suggesting that there is another level of functional heterogeneity within the IL-10-producing cells [145].

Regulation of IL-10 production in distinct lymphocytes is cell-type specific. While IL-10 production by Th2 cells may be a stable phenotype, Th1 and Th17 cells often transiently express IL-10, suggesting that there are on-and-off switch-like controls. Cell-type-specific IL-10 regulation may depend on the differential chromatin accessibility at different regulatory regions of the Il10 locus in different cell types. Master transcription factors may influence such epigenetic differences. Furthermore, unique expression pattern of a given transcription factor that is involved in IL-10 regulation in different cell subsets may also contribute to cell-type-specific IL-10 regulation. Finally, the levels of some IL-10 regulators may be dynamically expressed. For example, the expression of Bhlhe40 is highly sensitive to TCR stimulation through which IL-10 production may be differently regulated by this molecule at distinct activation stages. In addition, because of the dynamic nature of Bhlhe40 expression, the wild-type cells at certain stages when Bhlhe40 is under-expressed may behave like Bhlhe40 knockout cells; this may offer an explanation for different effects of Bhlhe40 deletion on IL-10 production in Th2 cells.

Transcription factor c-Maf is one of the most important regulators for IL-10 production in Th1, Th2, and Th17 cell subsets as well as in regulatory T cells, macrophages, and B cells [55–57, 146]. Similarly, Bhlhe40 can regulate IL-10 expression in distinct Th-cell subsets. Nevertheless, c-Maf and Bhlhe40 seems to cross-regulate each other’s expression [99, 100, 147]. The physiologic importance of the balance between c-Maf and Bhlhe40 may be well beyond IL-10 regulation. Indeed, while c-Maf suppresses IL-2 production, Bhlhe40 induces IL-2 production [100, 148]. Therefore, further investigation on the regulation of Bhlhe40 and c-Maf expression as well as their relationship in controlling the balance between anti-inflammatory and inflammatory Th-cell subsets will allow us to better understand immune regulation.

Il10-deficient mice spontaneously develop inflammatory bowel disease in the steady state with the presence of normal microbiota [149] and display more severe immunopathology after parasite infection when compared to wild-type mice [9, 19, 90]. In humans, mutations in IL-10 receptors have been associated with patients of inflammatory bowel disease [150]. Thus, targeting molecules and/or pathways that regulate IL-10 should be considered as effective strategies to treat many immunological diseases. For example, modulating IL-10 production and/or IL-10-producing Th cells, negatively or positively, may help tumor eradication or resolution of chronic inflammation, respectively. In general, understanding the molecular switches that control the balance and/or transition between inflammatory and anti-inflammatory states of distinct CD4 T-cell subsets is essential for designing new strategies to modulate immune responses in a cell-type- or disease-specific manner for the benefit of a wide range of patients in immunological disease conditions.

Acknowledgements

This research was supported by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases (No. 1-ZIA-AI001169).

Footnotes

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Contributor Information

Difeng Fang, Email: difeng.fang@nih.gov.

Jinfang Zhu, Email: jfzhu@niaid.nih.gov.

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PERMALINK

Molecular switches for regulating the differentiation of inflammatory and IL-10-producing anti-inflammatory T-helper cells

Difeng Fang

Jinfang Zhu

Abstract

Introduction

IL-10-producing Th cells in diseases

IL-10-producing Th2 cells in diseases

Fig. 1.

IL-10-producing Th1 cells in diseases

IL-10-producing Th17 cells in diseases

Genomic organization of the Il10 locus in T cells

Fig. 2.

Il10 locus in Th2 cells

Il10 locus in Th1 and Th17 cells

Shared molecular switches of inflammatory and IL-10 producing anti-inflammatory Th cells

IL-27 is a potent Il10 inducer

Fig. 3.

Other common Il10 regulators

Switches of inflammatory and IL-10-producing anti-inflammatory Th2 cells

Self-regulation of IL-10-producing Th2 cells

Switches of inflammatory and IL-10-producing anti-inflammatory Th1 cells

Cytokines that regulate IL-10-producing Th1 cells

Transcription factors that regulate IL-10-producing Th1 cells

Surface and intracellular molecules that regulate IL-10-producing Th1 cells

No self-regulation of IL-10-producing Th1 cells

Switches of inflammatory and IL-10-producing anti-inflammatory Th17 cells

Cytokines that regulate IL-10-producing Th17 cells

Transcription factors that regulate IL-10-producing Th17 cells

Cellular homeostasis and IL-10-producing Th17 cells

Self-regulation of IL-10-producing Th17 cells

IL-10-producing innate lymphoid cells (ILCs)

Conclusions

Acknowledgements

Footnotes

Contributor Information

References

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