Interleukin-1 (IL-1) consists of two distinct forms (IL-1α and IL-1β) and is a master cytokine of local and systemic inflammation (Dinarello et al., 2012). Primarily produced by monocytes, macrophages, and dendritic cells (DCs) in response to stimulation, IL-1β is involved in a variety of biological activities such as cell proliferation, differentiation, and apoptosis through its binding to functional IL-1 receptor I (IL-1RI) expressed on virtually all cells. Thus, IL-1β plays a role as a critical pathogenic mediator of many autoinflammatory, autoimmune, infectious, and degenerative diseases (Dinarello, 2011).

In human T-cell immunity, IL-1β has been identified as an essential cytokine with a role similar to that played by IL-6 in mice for Th17 differentiation, and is also important for expansion, in vivo survival, and effector function of IL-17-producing T cells (Acosta-Rodriguez et al., 2007; Lee et al., 2010). More recently, the importance of IL-1 signaling has been also emphasized in murine Th17 cells. Even though TGF-β and IL-6 are sufficient for murine Th17 differentiation, the IL-1RI knockout (KO) mouse is resistant to experimental autoimmune encephalomyelitis due to a failure to generate Th17 cells (Sutton et al., 2006; Chung et al., 2009). Further, IL-1β and IL-23 along with IL-6 are critical for generation of highly pathogenic Th17 cells in an autoimmune mouse model (Lee et al., 2012; Ronchi et al., 2016). Recent studies have demonstrated that IL-1β functions as a proinflammatory regulator of pathogenic human Th17 cells, which concomitantly produce IFN-γ and GM-CSF (Zielinski et al., 2012). Due to its potent effect as a proinflammatory cytokine, the biological activity of IL-1β is tightly regulated at multiple levels by diverse mechanisms including receptor antagonism through production of a decoy receptor and soluble forms of signaling receptors or accessory proteins (Garlanda et al., 2013a).

The IL-1R signaling complex includes the functional IL-1RI subunit and a signaling subunit, interleukin-1 receptor accessory protein (IL-1RAcP). Dimerization of the IL-1R1 and IL-1RAcP cytoplasmic Toll/IL-1R (TIR) domains initiates a signaling cascade through recruitment of adapter proteins (Garlanda et al., 2013b). The decoy IL-1RII has a short cytoplasmic tail lacking the signal-transducing TIR domain and acts as a molecular trap, capturing IL-1 with high-affinity and exerting a dominant-negative effect (Shirakawa et al., 1987). In contrast to ubiquitously expressed IL-1RI, the expression of IL-1RII is restricted to cells including monocytes, neutrophils, and B cells (Martin et al., 2017; Colotta et al., 1996; Colotta et al., 1993; McMahan et al., 1991). In addition, it was recently demonstrated that human-activated Treg cells and follicular regulatory T (T_fr) cells upregulate IL-1RII to attenuate their IL-1-dependent responses (Tran et al., 2009; Ritvo et al., 2017), suggesting a physiological significance for IL-1RII expression in immune regulation.

The physiological relevance of IL-1RII expression was investigated in autoimmune arthritis animal models using an IL-1RII conditional KO mouse. Deficiency of IL-1RII was found to exacerbate autoimmune arthritis by inhibiting IL-1 signaling in innate cells, such as macrophages and neutrophils (Martin et al., 2017; Shimizu et al., 2015). Our previous study showed that IL-1RII mRNA expression is markedly higher in IL-1RI⁺ memory CD4⁺ T cells compared to IL-1RI^- memory CD4⁺ T cells. Further, the negative regulatory role of IL-1RII was further evidenced by the significant augmentation of IL-17 production by IL-1RI⁺ memory CD4⁺ T cells in response to IL-1β and TCR stimulation after treatment with neutralizing IL-1RII antibody (Lee et al., 2010). Given its preferential expression on IL-17-producing IL-1RI⁺ CD4⁺ T cells as well as Tregs, IL-1RII has been suggested to play a pivotal role in maintaining the balance between Th17 and Treg cells. These cells are reciprocally interconnected in their development pathways and conversion between the two subsets is critical for pathogenesis and resolution of many inflammatory disorders (Zielinski et al., 2012; Basu et al., 2015; Gagliani et al., 2015). However, little is known about the molecular mechanism underlying IL-1RII expression by CD4⁺ T cells and its contribution to modulation of Th17 responses in humans.

Here, we provide novel insight into the immune regulatory role of decoy IL-1RII expressed on human CD4⁺ T cells by exploring its molecular mechanisms of action and analyzing its effect on Th17 responses. TCR stimulation potently induces functional IL-1RI on memory CD4⁺ T cells and a subset of IL-1RI⁺ CD4 T cells co-express decoy IL-1RII, conferring limited responsiveness to IL-1β. IL-RII expression is mediated through binding of a cooperative complex of the transcription factors NFAT and Foxp3 to its promoter. Differential expression of IL-1RI and IL-RII on activated CD4⁺ T cells defines unique immunological features via modulation of IL-1 β responsiveness. Of note, de novo expression of IL-1RI is aberrantly higher in synovial CD4⁺ T cells from RA patients, but TCR-mediated induction of IL-1RII expression is impaired compared to peripheral CD4⁺ T cells from RA patients or healthy controls. These findings underscore the regulatory role of decoy IL-1RII on IL-1β-mediated IL-1R signaling affecting Th17 responses and contributing to pathogenesis of Th17-related disorders.

Th17 cells are a unique subset of CD4⁺ effector T cells that elicit protective immune responses against extracellular bacterial and fungal pathogens (Gaffen, 2009). Th17 cells have been also implicated in the pathogenesis of many autoimmune disorders (Lee et al., 2012; Tabarkiewicz et al., 2015). Unlike conventional Th1 and Th2 cells, Th17 cells exhibit a substantial degree of instability, heterogeneity, and plasticity (Stadhouders et al., 2018). Many molecular mediators are closely involved in regulating plasticity of Th17 cells (Lee et al., 2012; Wang et al., 2015; Ichiyama et al., 2016; Stockinger and Omenetti, 2017). Among these, cytokines are critical determinants in the fate of Th17 cells. TGF-β and IL-6 give rise to nonpathogenic or beneficial Th17 cells, whereas IL-1β, IL-6 and IL-23 are involved in generation of pathogenic Th17 cells (Lee et al., 2012). Further, cell-fate mapping mouse models demonstrate that pathogenic Th17 cells can further convert into Th1 cells producing IFN-γ, but not IL-17 (ex-Th17 Th1 cells), in an IL-23-dependent manner (Hirota et al., 2011), whereas TGF-β is critical for transdifferentiation of Th17 cells into Treg cells (ex-Th17 Treg cells) during the resolution of inflammation or in the cancer microenvironment (Gagliani et al., 2015; Downs-Canner et al., 2017).

IL-1β is an essential cytokine for Th17 biology in humans that boosts Th17 production, induces pathogenic Th17 cells, and impairs the Th17-Treg balance (Basu et al., 2015). Activities of IL-1 are tightly controlled at different levels due to its potent proinflammatory effects. IL-1 receptor antagonist (IL-1Ra) and IL-1RII are negative regulators of the IL-1 system. IL-1Ra binds functional IL-1RI with no recruitment of IL-1RAcP, resulting in the repression of IL-1 binding in a competitive manner, whereas the decoy receptor, IL-1RII cannot transduce the signal initialized by the IL-1RI and IL-1Ra complex (Schlüter et al., 2018). We previously reported that the expression of IL-1RI and IL-1RII on CD4⁺ T cells is dynamically regulated in response to environmental factors such as TCR or cytokine stimulation, and such regulation influences Th17 cell responses (Lee et al., 2010). Furthermore, IL-1RII mRNA is expressed at a higher level in IL-1RI⁺CD4⁺ T cells than in IL-1RI^-CD4⁺ T cells and blockade by IL-1RII leads to reduced IL-17 production (Lee et al., 2010). However, the mechanism modulating IL-1RII expression and its role during the immune response remains unclear.

The expression of IL-1 and IL-1RII is tightly restricted under steady-state conditions, but is upregulated during inflammation (Schlüter et al., 2018). In contrast to IL-1RI, which is ubiquitously expressed at least at low levels, IL-1RII expression is confined to certain cell types, including monocytes, macrophages, some T cells in humans and microglial cells, osteoclasts and neutrophils in mice. Early studies showed that anti-inflammatory signals such as IL-4 and IL-13, as well as dexamethasone stimulate IL-1RII expression by monocytes and macrophages, suggesting its contribution to the anti-inflammatory effect (Colotta et al., 1996; Colotta et al., 1993). IL-1RII can be co-expressed with IL-1RI on the cell surface, albeit at a low copy number, and counterpoises the system by secluding IL-1 and IL-1RAcP from the neighboring signaling receptor IL-1RI (Colotta et al., 1993; Neumann et al., 2000). A recent study demonstrated that the cytosolic form of IL-1RII, expressed in certain types of cells, interacts with pro-IL-1α preventing cleavage and its calpain-dependent maturation and influences necrosis-induced sterile inflammation (Zheng et al., 2013). In a mouse model, IL-1RII deficiency on neutrophils and macrophages was found to aggravate K/BxN serum transfer-induced arthritis and collagen-induced arthritis by inhibiting IL-1 signals (Martin et al., 2017; Shimizu et al., 2015). However, the role of IL-RII on T cells remains to be understood.

We found that TCR-mediated induction of IL-1RI kinetically precedes IL-1RII expression by 12–24 hr and the induction of IL-1RII is predominantly observed in IL-1RI-expressing cells (Figure 2C and D). This suggests cis-regulation by IL-1RII involves its competitive binding to IL-1 and IL-1RAcP on CD4⁺ T cells under inflammatory conditions. Furthermore, treatment with IL-1β, but not other cytokines, further increased the expression of IL-1RII in TCR-stimulated CD4⁺ memory T cells, supporting the idea that there is a negative feedback loop of IL-1 signaling in CD4⁺ T cells (Figure 2—figure supplement 2B).

Of note, IL-1RII expression on memory CD4⁺ T cells was found to correlate with the dose of anti-CD3 mAb used for stimulation, whereas IL-1RI expression was significantly increased following weak anti-CD3 stimulation (100 ng/ml) (Figure 2E). Purvis et al., 2010 demonstrated that low-strength stimulation of human CD4⁺ T cells in a Th17-polarizing cytokine milieu strongly favors Th17 responses. They proposed that low Ca²⁺ signaling in CD4⁺ T cells under low-strength stimulation is preferential for the increase in binding of NFAT to the proximal region of the IL-17 promoter in CD4⁺ T cells, thereby enhancing IL-17 production. It should be noted that this enhancement of Th17 responses is observed only under treatment with Th17-polarizing cytokine such as IL-1β, IL-23, and TGF-β, suggesting a possible role of these cytokines in modulating IL-17 production (Purvis et al., 2010). Our finding may give another explanation as to why low-strength TCR stimulation favors Th17 responses in human CD4⁺ T cells, in that weak induction of IL-1RII leads to elevated IL-1β signaling, which causes increased RORγt activity and IL-17 production. Thus, we suggest that high-strength stimulation induces robust expression of IL-1RII on memory CD4⁺ T cells expressing IL-1RI and suppresses excessive IL-17 production via limiting IL-1β responsiveness (Figure 2F).

Considering the preferential expression of IL-1RII by TCR-induced Foxp3⁺ T cells (Figure 3; Tran et al., 2009; Mercer et al., 2010), it is reasonable to assume that Treg-related TFs are involved in IL-1RII gene expression. Foxp3 forms a multiprotein complex with many protein partners related to the regulation of transcription (Rudra et al., 2012). Among these Foxp3 partners, NFAT plays a key role in regulation of major Treg-related molecules such as CTLA-4, IL-2, and CD25 via direct binding of the NFAT/FOXP3 complex to the promotors of these genes (Wu et al., 2006; Hermann-Kleiter and Baier, 2010). Our findings allow the addition of IL-1RII to this list of genes. In vitro assays using the CsA, a drug targeting NFAT, show selective inhibition of IL-1RII expression on activating IL-1RI⁺ CD4⁺ T cells (Figure 4B). Furthermore, a VIVIT peptide derived from the calcineurin-NFAT-binding motif, PxIxIT, also significantly represses IL-1RII mRNA and protein expression (Figure 4C and D). Repression of NFAT activation by the VIVIT peptide is attributable to inhibition of NFAT binding to calcineurin affecting NFAT-dependent gene expression without affecting calcineurin phosphatase activity (Aramburu et al., 1998; Aramburu et al., 1999). On the contrary, enhanced induction of Foxp3 following treatment with 1,25(OH)two vitamin D3 was found to primarily augment the expression of IL-1RII and resultantly, the ratio of IL-1RII⁺ to IL-1RI⁺ activating CD4⁺ T cells was significantly increased (Figure 4H). This implies that 1,25(OH)two vitamin D3 causes limited IL-1β responsiveness.

An intriguing finding in the present study is that IL-1RII expression is cooperatively controlled by NFAT and Foxp3 in memory CD4⁺ T cells upon TCR stimulation (Figure 5B and C). The crystal structure analysis of the NFAT/FOXP3 complex revealed that the Wing1 domain, specifically amino acids 399–401 from FOXP3, physically interacts with the NFAT protein (Wu et al., 2006; Bandukwala et al., 2011). Based on this finding, Lozano et al., 2015 developed an inhibitory peptide encompassing the Wing1 domain, FOXP3 393–403, which specifically interferes with the NFAT/FOXP3 interaction, without affecting the capacity of NFAT to bind DNA. This peptide inhibits Treg activity via suppression of T-cell conversion into inducible Tregs and enhancement of T cell proliferation. FOXP3 393–403, originally developed for murine Tregs, also has a similar inhibitory effect on the interaction of human NFAT/FOXP3 (Lozano et al., 2015). Our data show that IL-1RII induction on activating IL-1RI⁺ CD4⁺ T cells was significantly reduced by FOXP3 393–403 to a degree comparable to the inhibition of CD25 expression (Figure 5A and C).

These findings were corroborated by our luciferase reporter and ChIP assays (Figure 5D and F). Comparative analysis of DNA sequences using Vista tools revealed that the IL-1RII gene has one small CNS region (−1309 to −1203) in its promoter. Of note, potentially one Foxp3 and two consecutive NFAT binding elements are closely located at positions −1236 to −1230 and −1209 to −1188, respectively, near the CNS region (Figure 5—figure supplement 1). The results of the IL-1RII promoter assay using Foxp3-overexpressing Jurkat T cells suggest that the binding of TFs, probably the NFAT/FOXP3 complex, in the CNS region is involved in increasing IL-1RII promoter activity. Transfection of truncated pGL4/IL-1RII plasmids without the CNS region and of a plasmid with mutated NFAT-binding sequences in the CNS region led to a significant reduction the promoter activity (Figure 5D). Furthermore, it has been demonstrated that in the IL2 promoter, the cooperative interaction between NFAT and Foxp3 involves direct protein–protein contacts between the DNA-binding domains of these transcription factors, at least some of which occur on composite DNA elements (ARRE sequences) with adjacent binding sites for the two transcription factors (Wu et al., 2006; Bandukwala et al., 2011; Hu et al., 2007). However, our ChIP data suggests that although the cooperative interaction between NFAT and Foxp3 is important for induction of IL-1RII, their major DNA-binding domains are located separately in the IL-1RII promoter (Figure 5D–F). This implies a more complex interaction occurs, possibly including tripartite partners and/or 3D looping of the genome. Furthermore, unlike the CD25 gene, there are no ARREs in the CNS region of IL-1RII promoter (Wu et al., 2006).

There are only a few studies describing IL-1RII expression on T cells. IL-1RII is preferentially expressed on TCR-stimulated Treg cells and thus, is a useful selective surface marker of activated human Treg cells (Tran et al., 2009; Mercer et al., 2010). Of interest, we found that IL-1RII expression is also induced by Treg-depleted memory CD4⁺ T cells, suggesting that IL-1RII expression is not strictly limited to activated Tregs. Sakaguchi and colleagues have suggested that FoxP3⁺CD4⁺ T cells consist of three distinct subsets: CD45RA⁺FoxP3^low (naive Treg), CD45RA^-FoxP3^high (effector Treg), and CD45RA^-FoxP3^low (Foxp3-expressing non-Tregs) CD4⁺ T cells. Of these, the CD45RA^-FoxP3^lowCD4⁺ T cell subset contains cells with Th17 potential (Miyara et al., 2009). Considering chemokine receptor and cytokine profiles of IL-1RI⁺CD4⁺ T cells (Figure 3C and D), it is possible that IL-1RI may be predominantly induced on the CD45RA^-FoxP3^lowCD4⁺ T-cell subset. Interestingly, IL-1RI also maintained significantly higher expression on activated human Foxp3⁺ Tregs compared to other T cell subsets despite its important role for Th17 responses (Tran et al., 2009; Mercer et al., 2010). Since Foxp3 is generally induced by TCR stimulation even on Treg-depleted conventional CD4⁺ T cells with Smad3 and NFAT dependent manner (Figure 3—figure supplement 3), strong TCR stimulation results in preferential expression of IL-RII, which limits IL-1β responsiveness and resultantly, reduces Th17 responses. In addition to the fact that the differentiation of Th17 and Treg cells is closely related (Zhou et al., 2008), both cells display instability and plasticity during immune responses; Foxp3⁺ Treg cells can be converted into IL-17-producing cells in certain inflammatory environments and may potentially contribute to pathogenesis of autoimmune diseases, whereas Th17 cells transdifferentiate into Treg cells during resolution of inflammation (Gagliani et al., 2015; Obermajer et al., 2014). Several studies suggest that some Th17 cells act like Tregs and this unique subset of Th17 cells are increased in tumor-bearing mice, human cancer patients (Gagliani et al., 2015; Downs-Canner et al., 2017; Krummey et al., 2014; Thibaudin et al., 2016; Jung et al., 2017), and during several inflammatory diseases. In our study, IL-1RI⁺IL-1RII⁺ cells were found to be similar in phenotype to Treg cells with relatively high expression of CD39, CD73, and CTLA-4 following TCR stimulation (Figures 3B and 6D). Because of their phenotype and potential modulatory function via CTLA-4 and IL-1RII, IL-1RI⁺IL-1RII⁺ cells may act as pivotal regulators of the Th17-cell-mediated inflammatory environment. Thus, the function and homeostatic capacity of IL-1RI⁺IL-1RII⁺ cells require further investigation.

Rheumatoid arthritis is a prototype autoimmune disease characterized by chronic inflammation of the joint synovial membrane (McInnes and O'Dell, 2010; McInnes and Schett, 2011). The disturbed Th17/Treg balance contributes to RA pathogenesis due to the strong pro-inflammatory response of preponderant Th17 cells and impaired Treg cells lacking immunomodulatory capacity, partly due to the cytokine circumstance (Niu et al., 2012; Wang et al., 2012; Noack and Miossec, 2014; Nie et al., 2013). The interesting observation in this study was diminished TCR-mediated induction of IL-1RII, and not IL-1RI, on memory CD4⁺ T cells from RA patients compared to the peripheral counterpart from healthy controls (Figure 7D), causing a significantly reduced ratio of IL-1RI⁺IL-1RII⁺ to IL-1RI⁺IL-1RII^- memory CD4⁺ T cells (Figure 7E). Of note, blocking of IL-1RII on memory CD4⁺ T cells of HCs led to increased IL-1β-mediated induction of IL-17 at a level comparable to that of RA patients (Figure 7F). Given the elevated level of IL-1β in RA synovial fluid and an important role of Th17 responses in RA pathogenesis (Kim et al., 2016; Kay and Calabrese, 2004), impaired induction of IL-1RII may be associated with modulation of IL-17 production in CD4⁺ T cells of RA patients under chronic autoreactive situations.

In summary, the current study provides new insight into the immune regulatory role of the decoy receptor, IL-1RII, expressed by human CD4⁺ T cells in response to TCR stimulation. Here, we investigated the molecular mechanisms underlying IL-1RII expression and analyzing its influence on Th17 responses and consequentially, the Th17/Treg balance. IL-RII expression is mediated molecularly by a cooperative complex of the NFAT and Foxp3 TFs. Further, differential expression of IL-1RI and IL-RII on activated CD4⁺ T cells imparts unique immunological features to these cells via modulation of IL-1β responsiveness. Together, these findings increase understanding of the modulatory mechanisms controlling the Th17 response, and of IL-1β-mediated IL-1R signaling and its contribution to the pathogenesis of autoimmune diseases such as RA.

All data generated or analysed during this study are included in the manuscript and supporting files.

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Author details

1. Dong Hyun Kim

   Laboratory of Autoimmunity and Inflammation (LAI), Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea

   Contribution

   Data curation, Software, Formal analysis, Investigation, Writing - original draft

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-2765-4376

2. Hee Young Kim

   1. Laboratory of Autoimmunity and Inflammation (LAI), Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea
   2. Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Republic of Korea
   3. Cancer Research Institute and Institute of Infectious Diseases, Seoul National University College of Medicine, Seoul, Republic of Korea

   Contribution

   Data curation, Formal analysis, Investigation, Methodology

   Competing interests

   No competing interests declared

3. Sunjung Cho

   Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Republic of Korea

   Contribution

   Data curation, Formal analysis, Investigation, Methodology

   Competing interests

   No competing interests declared

4. Su-Jin Yoo

   Department of Internal Medicine, Chungnam National University School of Medicine, 282 Munhwa-ro, Jung-gu, Daejeon, Republic of Korea

   Contribution

   Resources, Formal analysis, Investigation

   Competing interests

   No competing interests declared

5. Won-Ju Kim

   Department of Life Science, College of Natural Sciences and Research Institute for Natural Sciences, Hanyang University, Seoul, Republic of Korea

   Contribution

   Formal analysis, Investigation, Methodology

   Competing interests

   No competing interests declared

6. Hye Ran Yeon

   Department of Biochemistry and Molecular Biology, Department of Biomedical Sciences, and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea

   Contribution

   Resources, Investigation, Methodology

   Competing interests

   No competing interests declared

7. Kyungho Choi

   Department of Biochemistry and Molecular Biology, Department of Biomedical Sciences, and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea

   Contribution

   Conceptualization, Resources, Formal analysis, Methodology, Writing - review and editing

   Competing interests

   No competing interests declared

8. Je-Min Choi

   Department of Life Science, College of Natural Sciences and Research Institute for Natural Sciences, Hanyang University, Seoul, Republic of Korea

   Contribution

   Conceptualization, Investigation, Methodology, Writing - review and editing

   Competing interests

   No competing interests declared

9. Seong Wook Kang

   Department of Internal Medicine, Chungnam National University School of Medicine, 282 Munhwa-ro, Jung-gu, Daejeon, Republic of Korea

   Contribution

   Conceptualization, Resources, Data curation, Investigation

   Competing interests

   No competing interests declared

10. Won-Woo Lee

    1. Laboratory of Autoimmunity and Inflammation (LAI), Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea
    2. Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Republic of Korea
    3. Cancer Research Institute and Institute of Infectious Diseases, Seoul National University College of Medicine, Seoul, Republic of Korea
    4. Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine; Seoul National University Hospital Biomedical Research Institute, Seoul, Republic of Korea

    Contribution

    Conceptualization, Resources, Data curation, Formal analysis, Supervision, Funding acquisition, Validation, Investigation, Writing - original draft, Project administration, Writing - review and editing

    For correspondence

    wonwoolee@snu.ac.kr

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0002-5347-9591

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