IL-10 signaling in CD4+ T cells is critical for the pathogenesis of collagen-induced arthritis
© Tao et al.; licensee BioMed Central Ltd. 2012
Received: 21 August 2011
Accepted: 22 December 2011
Published: 22 December 2011
IL-10 is a very important anti-inflammatory cytokine. However, the role of this cytokine in T cells in the pathogenesis of collagen-induced arthritis is unclear. The purpose of this study was to define the role of IL-10 signaling in T cells in the pathogenesis of collagen-induced arthritis.
IL-10 receptor dominant-negative transgenic (Tg) and control mice were immunized with bovine type II collagen to induce arthritis. The severity of arthritis was monitored and examined histologically. T-cell activation and cytokine production were analyzed using flow cytometry. T-cell proliferation was examined by [3H]thymidine incorporation. Antigen-specific antibodies in serum were measured by ELISA. Foxp3 expression in CD4+ regulatory T cells (Tregs) was determined by intracellular staining or Foxp3-RFP reporter mice. The suppressive function of Foxp3+CD4+ Tregs was determined in vitro by performing a T-cell proliferation assay. The level of IL-17 mRNA in joints was measured by real-time PCR. A two-tailed nonparametric paired test (Wilcoxon signed-rank test) was used to calculate the arthritis and histological scores. Student's paired or unpaired t-test was used for all other statistical analyses (InStat version 2.03 software; GraphPad Software, San Diego, CA, USA).
Blocking IL-10 signaling in T cells rendered mice, especially female mice, highly susceptible to collagen-induced arthritis. T-cell activation and proliferation were enhanced and produced more IFN-γ. The suppressive function of CD4+Foxp3+ regulatory T cells was significantly impaired in Tg mice because of the reduced ability of Tregs from Tg mice to maintain their levels of Foxp3. This was further confirmed by transferring Foxp3-RFP cells from Tg or wild-type (Wt) mice into a congenic Wt host. The higher level of IL-17 mRNA was detected in inflammatory joints of Tg mice, probably due to the recruitment of IL-17+γδ T cells into the arthritic joints.
IL-10 signaling in T cells is critical for dampening the pathogenesis of collagen-induced arthritis by maintaining the function of Tregs and the recruitment of IL-17+γδ T cells.
Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of the joint capsule and synovial membrane which results in cartilage injury, bone erosion and eventually joint destruction and deformity . Collagen-induced arthritis (CIA) is a well-established animal model that has been studied extensively because of its similarities to human RA . Although the etiology of RA remains unknown, it has been reported that a functional imbalance between proinflammatory cytokines and regulatory T cells (Tregs) is a key mechanism that underlies joint inflammation and disease progression in CIA as well as RA .
IL-10 is a pleiotropic cytokine with important immune-regulatory functions . It has been implicated to have a potent anti-inflammatory role in several autoimmune disease models, including CIA . IL-10 suppresses the expression of inflammatory cytokines such as TNF-α, IL-6 and IL-1 by activated macrophages . IL-10 also affects T-cell proliferation and cytokine production [7, 8]. Indeed, IL-10 affects many of the cell types in the immune system; however, the precise role of IL-10 signaling in CD4+ T cells in the pathogenesis of CIA has not been addressed.
It has been demonstrated in both animal model and human studies that naturally occurring CD4+CD25+Foxp3+ Tregs play a critical role in the prevention of autoimmunity and inflammatory arthritis [9, 10]. Depletion of CD4+CD25+ T cells aggravated CIA [11, 12], whereas transferring CD4+CD25+ cells to a disease-bearing animal ameliorated arthritis . Although it has been well-documented that IL-10 can induce differentiation of naïve CD4+ T cells into CD4+IL-10+ Tr1 cells [13, 14], it is unclear whether IL-10 signaling in T cells affects the development or function of these Tregs.
Recently, a new subset of IL-17-producing CD4+ T cells, also called Th17 cells [15, 16], has been implicated as an important mediator in tissue inflammation . IL-17-deficient mice showed markedly suppressed CIA . Resistance to CIA in p19-/- mice correlated with an absence of IL-17-producing CD4+ T cells, suggesting that the IL-23-IL-17 axis rather than the IL-12-IFN-γ axis is essential in promoting the development of CIA . It has been reported that IL-10 suppresses Th17 cytokine secretion by macrophages and T cells in in vitro culture . However, the role of IL-10 signaling in T cells in the differentiation of Th17 cells and how this regulation affects the pathogenesis of CIA is less clear.
In this study, in which we studied previously described IL-10 receptor dominant-negative transgenic (Tg) mice , we showed that when T cells fail to respond to IL-10, mice develop more severe arthritis and T cells are more activated and proliferate more against type II collagen (CII) antigen. Moreover, the suppressive function of Tregs in these Tg mice was significantly impaired as a result of attenuated expression of Foxp3. IL-10 signaling in CD4+ T cells might affect the cytokine profiles of CD4+ T cells as well as γδ T cells. These results indicate that IL-10 signaling in T cells is the key to the pathogenesis of CIA.
Materials and methods
DBA/1 and C57BL/6 mice (Thy1.2 or Thy1.1 background) were purchased from The Jackson Laboratory (Bar Harbor, ME, USA) and maintained under specific pathogen-free conditions at the Yale University School of Medicine. DBA/1 background IL-10 receptor dominant-negative Tg mice were obtained by backcrossing C57BL/6 Tg mice  with wild-type (Wt) DBA/1 mice for nine generations. The H-2q/q and Tg genotypes were screened by PCR using tail DNA. The IL-10 GFP knockin mouse, designated IL-10-internal ribosomal entry site (IRES)-GFP-enhanced reporter (Tiger), and the Foxp3 red fluorescent protein (RFP) knockin mouse, designated Foxp3-IRES-mRFP (FIR) mice, were described previously [22, 23]. All the animal procedures were performed with the approval of the Institutional Animal Care and Use Committee of the Yale University School of Medicine.
Bovine CII for immunization, T-cell proliferation and ELISA, as well as Complete Freund's Adjuvant (CFA) and Incomplete Freund's Adjuvant (IFA), were all purchased from Chondrex (Redmond, WA, USA). BD GolgiPlug and antibodies for flow cytometry were purchased from BD (San Diego, CA, USA). A Foxp3 intracellular staining kit was purchased from eBioscience (San Diego, CA, USA). Cytokines and antibodies for T-cell differentiation in vitro were obtained from R&D Systems (Minneapolis, MN, USA). Phorbol 12-myristate 13-acetate (PMA) and ionomycin were purchased from Sigma-Aldrich (St Louis, MO, USA).
Collagen-induced arthritis model
The CIA model was employed as described previously . Briefly, 100 μg of bovine CII dissolved in 0.1 M acetic acid was emulsified with 100 μl of CFA containing 2 mg/ml inactivated Mycobacterium tuberculosis. Mice were sensitized by intradermal injection at the base of the tail and boosted at day 21 with the same dose of CII and IFA intradermally. Mice were scored blindly for disease severity every other day after the boost using a grading scale from 0 to 3 that was described previously . Each paw was graded with a maximum score of 12 per mouse.
Splenocytes from CIA mice were cultured with different concentrations of CII for 3 days. After pulsing with 1 μCi of [3H]thymidine per well for the last 18 hours, proliferation was measured as radioactivity incorporation (counts per minute (cpm)).
Splenocytes from CIA mice were stained with anti-CD3, anti-CD4, anti-CD8, anti-CD44 and anti-CD62L antibodies, and the surface markers for activation in CD4+ and CD8+ T cells were analyzed using an LSR II flow cytometer (BD).
ELISA for serum anti-CII antibodies and their isotypes
Serum samples were collected from different groups of immunized mice at different days postimmunization (days 0, 14, 28, 35 and 42), the levels of anti-CII antibody in different isotypes were measured by ELISA as described in our previous studies . Briefly, ELISA plates were coated with bovine CII (0.5 μg/well). After the plates were blocked with 5% fetal bovine serum-PBS, 1:800 diluted (with blocking buffer) mouse sera were added to duplicate wells and incubated for 2 hours at room temperature. The plates were then washed, and biotin-conjugated goat anti-mouse immunoglobulin G (IgG), IgG1 and IgG2a were added at a dilution of 1:2,000 for 1 hour, followed by the addition of streptavidin-horseradish peroxidase (Sigma-Aldrich). The plates were then developed, and antibody levels were measured as described previously .
Quantitative real-time PCR
Total RNA was isolated from joints by using the RNeasy Mini Kit (QIAGEN, Valencia, CA, USA). Genomic DNA was removed by digestion with DNase I. cDNA was synthesized using the iScript cDNA Synthesis Kit (Bio-Rad Laboratories, Hercules, CA, USA), and gene expression was examined using the Stratagene Mx3005P QPCR System with Brilliant SYBR Green QPCR Master Mix reagent (both from Agilent Technologies, Inc, Santa Clara, CA, USA). The data were normalized to a gapdh reference . The forward and reverse primers for il17 and gapdh were as follows : il17, TTTAACTCCCTTGGCGCAAAA, CTTTCCCTCCGCATTGACAC; and gapdh, TTCACCACCATGGAGAAGGC, GGCATGGACTGTGGTCATGA.
Intracellular Foxp3 and cytokine staining
Single-cell suspensions were prepared from spleens, lymph nodes or thymi and stained with surface CD4 and CD25. After being fixed with freshly prepared fixation/permeabilization solution at 4°C for at least 30 minutes in the dark, cells were blocked with Mouse BD Fc Block (BD) in permeabilization buffer at 4°C for 15 minutes and stained with anti-Foxp3 antibody at 4°C for 30 minutes. For intracellular cytokine staining, cells were stimulated with PMA plus ionomycin in the presence of brefeldin A for 4 hours. Cytokine production was measured as described previously.
Enriched CD4+ T cells were sorted into a CD4+CD25+ subset as the regulatory cells and a CD4+CD25- subset as the responder cells. T-cell-free splenocytes treated with mitomycin C were used as antigen-present cells (APCs). The responder cells were cultured with the regulatory cells at ratios of 1:1, 1:0.5, 1:0.25 and 1:0.125 or without the regulatory cells as the positive control in the presence of 2 μg/ml anti-CD3 antibody for 3 days in 96-well U-bottom plates, and APCs were added with the responder cells at a 5:1 ratio. After pulsing with 1 μCi of [3H]thymidine per well, proliferation was measured as radioactivity incorporation. The suppressive efficiency was calculated using the following formula: percentage suppression = (cpm of positive control) - (cpm of experiment)/(cpm of positive control) × 100.
CD4+RFP+ Tregs were sorted from the spleens of B6 Thy1.1 IL-10 dominant-negative receptor Tg and Wt mice and were transferred into B6 Thy1.2 Wt mice at equal cell numbers. One day after transfer mice were immunized with CFA and bovine CII as described above. One week after immunization Foxp3 expression in transferred cells was analyzed by checking the levels of RFP.
On day 58 after CIA induction, mice were killed and their paws were dissected free and used for histologic examination. The joints were immediately fixed in 10% buffered formalin and decalcified in a decalcifying solution for about 3 to 5 days . The tissues were then processed and embedded in paraffin. Five-micrometer tissue sections were prepared and stained with H & E using standard methods. All sections were stained at the Yale Pathology Laboratory. Sections were blindly observed and scored by histologists. Five arthritis severity factors were assessed using a grading scale from 0 (normal) to 5 (severe), based on a previously described scoring system .
Data presented are means ± SEM. Statistical testing was two-tailed with a 5% level of significance. A two-tailed nonparametric paired test (Wilcoxon signed-rank test) was used to analyze the arthritis and histologic scores. Student's paired or unpaired t-test was used for all other statistical analyses (InStat version 2.03 software; GraphPad Software, San Diego, CA, USA).
Blocking IL-10 signaling in T cells rendered mice highly susceptible to collagen-induced arthritis
IL-10 signaling in T cells controls T-cell activation and proliferation responses in collagen-induced arthritis mice
Impaired suppressive function of regulatory T cells from transgenic mice
IL-10 signaling in T cells is required for maintenance of Foxp3 expression
Increased IL-17+ γδ T cells and joint IL-17 expression in transgenic mice
IL-10 signaling in T cells has no effect on antigen-specific antibody response
The CIA has been used as a model for studying the pathogenesis and potential application of novel therapeutic agents for human RA. Both T and B cells are essential for the development of RA [34, 35], and IL-10 plays different roles in regulating the function of T and B cells . It is therefore important to study the unique role of IL-10 signaling in T cells (without affecting B cells) in the pathogenesis of CIA. In this study, we demonstrated that IL-10 signaling in T cells play a critical role in the pathogenesis of CIA by affecting the function of Tregs by stabilizing the expression of Foxp3.
To target IL-10 signaling selectively in T cells, a unique IL-10 receptor dominant-negative Tg mouse was recently developed with the Tg under the control of CD4 promoter, which lacks the CD8 silencer element and therefore is expressed in both CD4+ and CD8+ T cells . In these mice, CD4+ and CD8+ T cells expressed high levels of the Tg IL-10Ra, which lacks the cytoplasmic domain. As this receptor functions as a dominant-negative receptor, its responsiveness to IL-10 is attenuated in these T cells. Using these mice, we demonstrated that Tg mice developed more severe arthritis upon induction in the absence of IL-10 signaling (Figure 1). This was especially true for female mice. Even in susceptible strains, female Wt mice are more resistant than males, and the underlying mechanisms have not been studied systematically. Our observation that blockade of IL-10 signaling in T cells rendered female mice highly susceptible to CIA may shed some light on the molecular mechanisms of the gender differences. Of course, we did not rule out the possibility that IL-10 signaling might also affect the male mice if these mice were immunized with lower doses of CII and/or subdoses of adjuvant. Further studies are needed to explore this possibility.
CD4+ T cells play an essential role in the pathogenesis of CIA as well as RA. Autoreactive T cells are normally controlled by Tregs and other regulatory mechanisms under normal circumstances, whereas in autoimmune diseases Treg dysfunction causes autoreactive T-cell proliferative responses and tissue damage . As one of the key suppressive cytokines, IL-10 plays an important role in controlling T-cell responses. Indeed, though T cells were unable to respond to IL-10, they were more activated and proliferated more vigorously upon CIA induction, with a a more pronounced Th1 response (Figure 2). Our data suggest that a potential mechanism for this enhanced T-cell response could be the dysfunction of Tregs. Although IL-10 signaling in T cells was not required for the development of nTregs (Figures 3A and 4A), we clearly have demonstrated that the suppressive function of Tregs was significantly impaired in the absence of IL-10 signaling (Figures 3C and 3D).
Several elements are critical for the function of Tregs, including IL-10, TGF-β and CTLA-4 . To define which factor was critical for the function of Tregs in connection of IL-10 signaling in T cells, we analyzed the levels of IL-10, TGF-β and CTLA-4 in Tregs of Wt and the Tg mice. To our surprise, no significant differences were detected between these two populations of Tregs (Figure 4), implying that IL-10 signaling in T cells was not required for the expression of these factors.
Foxp3 is a critical factor that determines not only the development and differentiation but also the suppression function of Tregs. Expression of Foxp3 can be regulated by multiple factors, including inflammatory cytokines . One of the striking findings of our study is that we have demonstrated that in the absence of IL-10 signaling in T cells, the expression levels of Foxp3 were reduced upon immunization, on the basis of both ex vivo studies (Figure 4A) and Foxp3-RFP T-cell adoptive transfer experiments (Figures 4F and 4G). This phenotype was observed in C57BL/6 mice as well as in DBA/1 mice, suggesting that Foxp3 downregulation in Tg mice upon immunization may be associated with the disease mechanism in CIA (data not shown). By taking advantage of our Foxp3-RFP reporter mice, we were able to isolate a pure population of Tregs and track these cells in the congenic hosts. We speculated that upon immunization, inflammatory cytokines might target Tregs and regulate expression of Foxp3. One of the critical functions of IL-10 signaling in these Tregs probably was to maintain the expression of this key molecule. Therefore, our results collectively indicate that IL-10 signaling in T cells is critical for the function of Tregs by maintaining the expression level of Foxp3. Although Foxp3 is an X-linked gene, no significant difference was observed in the expression levels of Foxp3 between male and female mice (data not shown). Further studies are needed to define the molecular mechanisms underlying how the IL-10 signaling pathway maintains the expression of Foxp3.
IL-17 has been defined as a critical cytokine that mediates autoimmune inflammation, especially in CIA and RA . This has been evidenced by a series of studies using different gene-deficient mice, including p19-/-, inducible costimulatory molecule (ICOS-/-) and IL-17-/- mice [18, 19, 40]. Indeed, the expression levels of IL-17A were found to be significantly increased in the joints of Tg mice, which correlated with severe arthritis (Figure 5). Interestingly, the increased levels of IL-17 were not derived from CD4+ T cells; rather, they were most likely derived from γδ T cells (Figures 5D and 5E). Our results are consistent with those of previous studies in that Vγ4 γδ T cells provided IL-17A in the pathogenesis of CIA . How does IL-10 signaling in CD4+ T cells affect the production or recruitment of IL-17A-producing γδ T cells is unclear at present. Several possibilities might explain our findings. IL-10 signaling promoted both thymic and peripheral CD4+ T cells to produce IL-17A in naïve, but not in immunized, mice (Figure 5A), indicating a possibility that IL-10 signaling might change the threshold of IL-17 expression by CD4+ T cells. The increased percentage of IL-17+ γδ T cells in the draining lymph nodes of CIA mice could be a result of more local differentiation, more recruitment from other tissues, or both. Whether increased IL-17 production from CD4+ T cells in naïve mice has any impact on IL-17 production by γδ T cells upon immunization remains to be determined.
We have to emphasize that IL-10 signaling in T cells did not affect T-cell-B-cell collaboration or the production of CII-specific antibodies (Figure 6). IL-10 has been defined as a B-cell-stimulating factor and can promote antibody production [42, 43]. Because the function of T cells but not B cells was affected in Tg mice , it was not surprising that we saw no differences in autoantibody production between Wt and Tg mice. More generally, this Tg mouse may provide a unique model in which to study the dysfunction of T cells without affecting antibody responses.
Our study clearly demonstrates that IL-10 signaling in T cells is critical for the pathogenesis of CIA by maintaining the level of Foxp3 and consequently contributing to the dysfunction of Tregs as well as to the increased expression level of the innate source of IL-17A by γδ T cells. Enhancement of IL-10 signaling in T cells may regulate the function of Tregs, which can dampen the harmful autoimmune responses.
Our results demonstrate a critical role of IL-10 signaling in T cells in the pathogenesis of CIA. Without IL-10 signaling, T cells, especially Tregs, lost their suppressive function, which in turn failed to control CD4+ T-cell activation. Enhancement of IL-10 signaling in T cells might serve as a therapeutically sound approach to the treatment of RA as well as other autoimmune inflammatory diseases.
JT, PhD, associate research scientist; MK, PhD, postdoctoral fellow; JH, PhD candidate; JC, professor; RF, professor; ZW, assistant professor; ZH, professor; LZ, professor; ZY, professor; ZH, research associate; XJ, research associate.
Complete Freund's Adjuvant
enzyme-linked immunosorbent assay
green fluorescent protein
- H & E:
hematoxylin and eosin
Incomplete Freund's Adjuvant
polymerase chain reaction
This research was made possible by a grant from the American College of Rheumatology Research and Education Foundation Within Our Reach: Finding a Cure for Rheumatoid Arthritis campaign (to RAF and ZY). Dr Yin is supported by the National Natural Science Foundation of China (30725015 and 30890143), the National Basic Research Program of China (2010CB529104) and the International S&T Cooperation Program of China (2010DFB34000). Dr Yin was also supported by the Program of Introducing Talents of Discipline to Universities (B08011) and 07ZCKFSH03600 (Tianjin Science and Technology Commission). ZHong was supported by 09ZCKFSH08200 (Tianjin Science and Technology Commission).
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