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* Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan;
Department of Dermatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan;
Tokyo Metropolitan Institute for Gerontology, Itabashi-ku, Tokyo, Japan; and
Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi, Japan
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Introduction |
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It has been shown that CD25, the IL-2R 
-chain, is not only a useful molecular marker for natural CD4+ Treg but also an essential molecule for their development and function as an indispensable component of the high-affinity IL-2R. For example, IL-2-, CD25-, or CD122 (IL-2R 
-chain)-deficient mice develop fatal autoimmune/inflammatory disease similar to Foxp3 deficiency (10, 11, 12). Neutralization of circulating IL-2 for a limited period selectively reduces the number of CD25+CD4+ Treg and elicits autoimmune disease similar to the one produced by depletion of CD25+CD4+ Treg (13). In contrast, there is accumulating evidence for the existence of regulatory activity in the CD25–CD4+ T cell population. For example, CD25–CD45RBlowCD4+ T cells in rodents and CD25–CD45RO+CD4+ T cells in humans contain cells expressing Foxp3/FOXP3 at a low level (6, 9, 14). CD25–CD4+ T cells bear an autoimmune-suppressive activity in various animal models of autoimmune disease, although the activity is generally weaker than that of natural CD25+CD4+ Treg (15, 16, 17). It must be determined then to what degree CD25–CD4+ Treg contribute to the maintenance of natural self-tolerance and how severe the autoimmune diseases will be, in particular what spectrum of autoimmune/inflammatory disease will develop, when both CD25+ and CD25– Foxp3-expressing Treg are depleted from the normal immune system.
CD25+CD4+ Treg express GITR (glucocorticoid-induced TNFR family related gene/protein) at higher levels than other T cells or B cells; and neonatal administration of anti-GITR mAb induces autoimmune disease similar to the one produced by depletion of CD25+CD4+ Treg (18). In addition, CD25–GITRhigh T cells were shown to exert suppressive activity in organ transplantation and inflammatory bowel disease (19, 20). In this study, we show that specific, stable expression of GITR occurs in the majority of Foxp3-expressing CD25+ and CD25– Treg in the thymus and periphery. With high-level expression of GITR as a reliable marker for Foxp3+ natural Treg, we show that both CD25+ and CD25– Treg in the thymus and periphery contribute to the maintenance of natural self-tolerance and hence prevention of autoimmune disease but to different degrees, and that by depletion of Foxp3+ GITRhigh cells, we can activate even weak or rare autoimmune T cell clones and cause severe and wide-spectrum autoimmune/inflammatory diseases as in IPEX. Importantly, this thorough depletion of Foxp3+ GITRhigh T cells also produces a variety of novel autoimmune/inflammatory diseases that immunopathologically resemble human inflammatory diseases, such as giant cell myocarditis, which have been suspected to be autoimmune in etiology. The results indicate that reduction or functional anomaly of natural Treg can be a cause of such rare but fatal autoimmune/inflammatory diseases, providing a clue to their etiology, pathogenetic mechanism, treatment, and prevention.
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Materials and Methods |
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Eight-week-old BALB/c mice and 6-wk-old BALB/c nude mice were purchased from Japan SLC. Eight-week-old NOD mice and 6-wk-old NOD-SCID mice were purchased from CLEA Japan. They were treated in accordance with the institutional guidelines for animal welfare.
Reagents
PE-labeled anti-CD25 (PC-61), FITC-conjugated-anti-CD4 (L3T4), anti-CD8 (53–6.7), PerCP-Cy5.5-anti-CD4 (L3T4), biotinylated anti-CD25 (7D4), anti-CD4 (L3T4), anti-CD8 (53–6.7), anti-CD19 (1D3), PE-labeled rat IgG2a (isotype control for Foxp3 staining), and PE-labeled streptavidin were all purchased from BD Pharmingen; allophycocyanin-conjugated streptavidin was obtained from eBioscience; and biotinylated polyclonal anti-GITR was obtained from Genzyme-Techne. Biotinylated anti-GITR mAb (DTA-1) was reported previously (18). PE-labeled anti-mouse Foxp3 mAb was obtained from eBioscience and used for intracellular staining according to the manufacturer’s instructions. Stained cells were analyzed by a FACSCalibur (BD Biosciences). FITC-conjugated anti-mouse IgG (H+L) was obtained from Jackson ImmunoResearch Laboratories. Alexa Fluor 568-conjugated phalloidin was obtained from Molecular Probes. Anti-PE microbeads were obtained from Miltenyi Biotec.
Preparation of lymphocytes
CD25+ or GITRhigh cells were depleted using mAbs and complement as described previously (21). CD4+ T cells, CD8+ T cells, or B cells were purified by the MACS system (Miltenyi Biotec), using biotinylated anti-CD4, anti-CD8, or anti-CD19, respectively, with PE-labeled streptavidin and anti-PE microbeads. Other T cell subpopulations were prepared as described previously (19). For assessing GITR expression on the residual cells after anti-GITR (DTA-1) or anti-CD25 (7D4)+C (complement)-treatment or C-treatment alone, they were incubated again with DTA-1 and 7D4, washed, and stained with rabbit polyclonal biotinylated anti-murine GITR Ab.
Quantitation of mRNA expression by real-time RT-PCR
Quantitation of Foxp3 and HPRT mRNA by real-time PCR was described previously (6).
Histopathology
Myocarditis and other autoimmune diseases were histologically evaluated and graded as described previously (21, 22, 23).
Immunohistochemistry of heart
For immunohistochemistry of heart, myocarditis-afflicted nude mice or normal 8-wk-old BALB/c mice were sacrificed as described, and heart was obtained, which was washed with cold PBS and mounted in OCT compound and snap frozen. Infiltrating cells in the hearts with myocarditis were analyzed by staining frozen sections with rat anti-CD4 (L3T4), rat anti-CD8a, rat anti-B220 (CD45R), and rat anti-Mac1 (CD11b), which were obtained from BD Pharmingen, followed by HRP-conjugated hamster anti-rat IgG (H+L) (Kirkegaard & Perry Laboratories) as the secondary Ab, counterstained by hematoxylin. Controls were stained with the secondary Ab alone. For indirect immunohistochemistry, normal heart from BALB/c mice was prepared as described above and fixed with acetone or 4% paraformaldehyde. Sections were first incubated with 3% FBS in PBS for 1 h, then with 10-times-diluted sera from myocarditis-afflicted or control mice for 1 h at room temperature, and with FITC-conjugated anti-mouse IgG (H+L) with Alexa Fluor 568-conjugated phalloidin counter staining. Fluorescence images were taken by a Zeiss LSM510 confocal microscope attached to an axiovert inverted microscope.
Western blotting
Organs/tissues from female 8-wk-old BALB/c mice were homogenized with a Polytron homogenizer in lysis buffer containing 150 mM NaCl, 25 mM Tris-HCl (pH7.5), 5 mM EDTA (pH 8.0), 10% IGEPAL CA-630 (Sigma-Aldrich), and protease inhibitor (WAKO). SDS-PAGE was performed in either 12 or 7.5% acrylamide gel, or in 10% gradient gel made from Prosieve 50 gel solution (BioWhittaker Molecular Applications) with Broad Range (Bio-Rad) as a size marker. Separated proteins were then blotted onto a polyvinylidene difluoride membrane, Immobilon (Millipore) using a semidry-transfer system. The transferred membrane was blocked with 5% skim milk and incubated with serially diluted sera from 1/30 to 1/3000, followed by detection with HRP-conjugated anti-mouse IgG (H+L) (Kirkegaard & Perry Laboratories) and ECL (Amersham Biosciences).
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Results |
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Cytofluorometric analysis by intracellular Foxp3 staining and cell surface staining of CD25 or GITR showed that >95% of Foxp3+CD4+ T cells were GITRhigh, and that 
75% of them were CD25+ (Fig. 1a). CD25+CD4+ T cells in normal naive mice constitutively express CTLA-4 (24); and the majority of CTLA-4+CD4+ T cells in normal naive mice were GITRhigh (data not shown). Foxp3+ cells constituted <1% of CD8+ T cells (data not shown). Thus, the majority of Foxp3+CD4+ T cells, which can be CD25+ or CD25–, are GITRhigh in normal naive mice.
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6 and 2% of CD4+ T cells after anti-CD25+C or anti-GITR+C-treatment, respectively (Fig. 1b). The result correlated with the level of Foxp3 mRNA expression: anti-GITR+C-treatment reduced the level to 1/30 of control CD4+ cells and to a level equivalent to that of CD8+ T cells, whereas anti-CD25+C-treatment reduced the level only to 1/10 of controls (Fig. 1c). Notably, transfer of anti-GITR+C-treated cell suspensions (GITRlow) resulted in reduced survival of the recipient nude mice (50% of mice died by 40 days after transfer), whereas transfer of anti-CD25+C-treated cells (i.e., CD25–) or C-treated control cells (i.e., whole T cells) did not affect the survival (Fig. 1d).
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To determine the cause of the death and the extent of autoimmunity/inflammation in nude mice transferred with GITRlow T cells, mice were macroscopically and histologically examined when they became debilitated, cachectic, or cyanotic (Fig. 2, Table I). Debilitated mice frequently exhibited marked dilatation of the heart (Fig. 2a), pleural effusion, ascites, and congested liver, indicating severe heart failure as the cause of death. Histological examination revealed a marked infiltration of mononuclear inflammatory cells, appearance of multinucleate giant cells, and destruction of cardiac myocytes (Table I, Group B and Figs. 2, b and c, and 3). Infiltrating cells were predominantly Mac1+ cells (macrophages) and CD4+ T cells, and to a lesser extent, CD8+ T cells and B220+ cells (B cells) (Fig. 2e). Transfer of CD25– cells did not affect the survival or induce myocarditis (Table I, Group C).
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This induced myocarditis is a T cell-mediated autoimmune disease because adoptive transfer of spleen cells, especially CD4+ T cells, was able to secondarily transfer the disease to a fresh cohort of syngeneic athymic nude mice (Fig. 2i). When the donor mice were myocarditis-free but developed other organ-specific autoimmune diseases (such as gastritis, thyroiditis, and oophoritis; Table I), the cell transfer failed to elicit myocarditis in the recipients but successfully produced the latter (Ref.25 and data not shown). Transfer of the sera alone from myocarditis-afflicted mice failed to produce myocarditis or other diseases in athymic or euthymic mice (data not shown).
Thus, transfer of GITRlow cells, in contrast with that of CD25– cells, induced in BALB/c nude mice T cell-mediated autoimmune myocarditis that immunopathologically resembled giant cell myocarditis in humans (26, 27). The transfer also produced other autoimmune diseases (such as gastritis, thyroiditis, sialadenitis, and hepatitis) at high incidences even when early death due to myocarditis made it difficult to accurately assess the incidences of other slowly developing autoimmune/inflammatory diseases in BALB/c nude recipients (Table I).
We showed in a previous report that transfer of GITRlow T cells produced autoimmune diseases in syngeneic BALB/c nude mice without reduction of survival (18). The difference between the previous and the present results could be attributed to the strains of nude mice used. The BALB/c nude substrain previously used (i.e., BALB/cClea-nu) developed nonfatal and histologically mild myocarditis at 20% incidence after transfer of GITRlow T cells (18). There are subtle differences among substrains of BALB/c nude mice in the incidence, severity, and spectrum of autoimmune disease induced by removal of CD25+CD4+ T cells (25). BALB/cSlc nude mice and BALB/cSlc mice, which were used in the present experiments, are more susceptible than other BALB/c substrains to various organ-specific autoimmune diseases. The BALB/cSlc athymic and euthymic strains in our facility were ensured to be specific pathogen-free, in particular, free of Coxsackie virus and other viruses that are reported to cause myocarditis (28).
GITRhighCD25–CD4+ T cells and CD25+CD4+ T cells in normal naive mice bear autoimmune-suppressive activity
The development of autoimmune myocarditis in nude mice after transfer of GITRlow cells, but not CD25– cells, cannot be due to different numbers of autoimmune effector T cells transferred, because transfer of GITRlow cells at a dose much smaller than CD25– T cells could still induce myocarditis (Table I, Group B). Furthermore, CD25+GITRlow cells, which exist in GITRlow but not in CD25– cells, are not "heart-specific effector cells" because their depletion from GITRlow cells by mixed mAbs of anti-CD25 and anti-GITR+C did not reduce the incidence of autoimmune myocarditis (Table I, Group D; and Fig. 3). It is more likely, therefore, that CD25–GITRhigh cells bear an autoimmune regulatory activity, and anti-GITR+C-treatment depletes not only CD25+ Treg but also CD25– Treg. To examine this possibility further, we cotransferred to nude mice the same number of GITRlow cells and CD25– cells or an equivalent number of CD25–CD4+ cells, and assessed the occurrence of myocarditis and other autoimmune diseases (Table I, Groups F and G; and Fig. 3). The cotransfer effectively suppressed the development of myocarditis, but not other autoimmune diseases, indicating that GITRhighCD25–CD4+ T cells in the CD25–CD4+ population could suppress myocarditis but not the occurrence of other diseases. Apparently, this myocarditis-specific suppression by CD25–CD4+ T cells also makes it unlikely that severe disease induction by GITRlow cells is due to possible activation of GITRlow cells by agonistic DTA-1 attached to them during in vitro Ab treatment for depletion of GITRhigh cells (18).
Compared with CD25–CD4+ T cells, CD25–CD8+ T cells were much less effective in this autoimmune suppression, whereas a small number of CD25+CD4+ T cells completely suppressed the development of every autoimmune disease (Table I, Groups E, G, and H; and Fig. 3).
Taken together, these results indicate that not only CD25+CD4+ T cells but also GITRhighCD25– cells in the CD25–CD4+ population hold an autoimmune-suppressive activity. Compared with the potent autoimmune-suppressive activity of the former, the latter is sufficient in number or suppressive activity to inhibit the development of myocarditis but insufficient to suppress other autoimmune diseases such as gastritis, thyroiditis, and oophoritis, which can be easily induced in BALB/c mice by depletion of CD25+CD4+ Treg alone (3).
Acceleration of the onset of T1D and induction of other autoimmune diseases in NOD-SCID mice by the transfer of GITRlow T cells
Diabetes-prone NOD mice also harbor CD25+ and CD25– Foxp3-expressing CD4+ T cells, the majority (>97%) of which were GITRhigh, comparable to what was shown in BALB/c mice (Fig. 4a). To determine then whether the development of severe autoimmune diseases after removing GITRhigh T cells is unique to BALB/c mice, we transferred GITRlow or CD25– T cells from NOD mice to NOD-SCID mice (Table II). Mice receiving GITRlow cell transfers began to lose body weight 2 wk after cell transfer (Fig. 4b). The onset of diabetes was accelerated in these mice, which started to develop hyperglycemia (>350 mg/dl) within 1 mo after cell transfer, compared with >2 mo for CD25– cell-transferred mice (Fig. 4c). GITRlow-cell-transferred mice also developed severe diarrhea with debilitation, whereas CD25– cell-transferred mice did not (Fig. 4b). Histologically, colitis, myositis of skeletal muscle (but not the myocardium), and hepatitis with inflammatory destruction of the portal area frequently developed in GITRlow cell-transferred NOD-SCID mice despite their early demise after cell transfer due to severe diarrhea and debilitation (Fig. 4d and Table II). Both groups developed multiple organ-specific autoimmune diseases including gastritis and thyroiditis (Table II). Thus, GITRhigh cell populations would include both CD25+ and CD25– Treg in NOD mice as well, as shown in BALB/c mice. These data, specifically with respect to myositis, colitis, and hepatitis, should suggest a similar phenomenon to that which was observed in BALB/c mice.
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Single-cell staining revealed that Foxp3+ thymocytes comprised 5–6% of CD4-SP thymocytes (Fig. 5a). The majority (>98%) of Foxp3+CD4-SP thymocytes were GITRhigh, compared with 70% of Foxp3+ thymocytes as being CD25+ (Fig. 5a).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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The GITRhigh cell depletion induced autoimmune myocarditis at a high incidence in BALB/c mice in addition to other organ-specific autoimmune diseases, such as gastritis and thyroiditis, which are commonly produced by depletion of CD25+ Treg. The myocarditis accompanied the development of autoantibodies specific for cardiac myosin (23, 29, 30). Like gastritis and thyroiditis induced by Treg depletion, it is a bona fide autoimmune disease because T cells, especially CD4+ T cells, were able to transfer the disease adoptively to naive nude mice (25, 29). It has been shown that autoimmune myocarditis can be induced in animals by a variety of approaches. For example, it can be produced in genetically susceptible strains of mice by immunization with cardiac myosin along with potent adjuvant, repeated inoculation of dendritic cells pulsed with myosin peptides, or infection with Coxsackie virus and other cardiotropic viruses (23, 28, 29, 30, 31). BALB/c mice deficient of PD-1, a coinhibitory molecule expressed by activated T and B cells, spontaneously develop cardiomyopathy accompanying autoantibody specific for cardiac troponin (32). CTLA-4 or TGF--deficient mice also succumb to severe myocarditis (33, 34, 35, 36). Furthermore, NOD mice expressing transgenic human HLA-DQ8 in the absence of endogenous class II MHC spontaneously develop severe myocarditis accompanying autoantibody specific for cardiac myosin H chain (37). Thus, autoimmune myocarditis develops as the result of altered antigenicity or excessive presentation of cardiac self-Ags, and also as the consequence of alteration in the generation or peripheral control of self-reactive lymphocytes specific for cardiac self-Ags. Assuming that the various forms of myocarditis in humans are heterogeneous in etiology, it remains to be determined which of the mechanisms revealed in animals are relevant to particular types of myocarditis in humans. It is of note in this regard that a type of giant cell myocarditis and dilated cardiomyopathy in humans is frequently associated with other organ-specific autoimmune diseases, such as T1D and thyroiditis (26, 27). Given the fact that developmental or functional anomaly of natural Treg can be a cause of autoimmune disease as demonstrated in IPEX and possibly in other autoimmune polyendocrinopathy syndromes (4, 38), our present results indicate that one of the causes of giant cell myocarditis in humans can be genetically or environmentally induced abnormality in natural Treg. In this way, the disease would share a common pathogenetic basis with other more common organ-specific autoimmune diseases such as T1D, chronic thyroiditis, and autoimmune gastritis (26, 27). Myocarditis in CTLA-4 or TGF- deficiency could be attributed to defective development or function of natural Treg because both molecules are engaged in the maintenance and activation of natural Treg (24, 39, 40, 41, 42, 43).
A key finding in this study is that when the reduction of natural Treg is very severe, novel autoimmune diseases develop, which fail to occur with mild Treg reduction; e.g., development of autoimmune myocarditis in BALB/c mice after depletion of GITRhigh T cells but not CD25+ T cells alone. We have shown that whatever the procedures of reducing the number or function of natural Treg are, the reduction produces a similar spectrum of organ-specific autoimmune diseases in a particular strain of mice; for example, gastritis, oophoritis, thyroiditis, and other autoimmune diseases in that order of incidences in BALB/c mice (13, 44). Similarly, NOD mice are genetically prone to develop T1D and thyroiditis; and Treg reduction accelerates the occurrence of T1D and thyroiditis in NOD mice (13, 45). These results, when taken together, indicate that the phenotype and severity of autoimmune/inflammatory diseases elicited by Treg reduction depends, at least in part, on the degree of Treg reduction, but also on the genetic background of the hosts. The more severe the Treg reduction, the wider the spectrum of autoimmune diseases in a genetically determined hierarchical pattern. Furthermore, it is likely that normal mice harbor those self-reactive T cells (e.g., heart-reactive T cells in BALB/c mice), which may be low in number or pathogenicity and therefore easily subjected to suppressive control in the physiological state even by CD25– Treg.
The present experiments demonstrated that both CD25+ and CD25–CD4+ Treg actively engage in the maintenance of natural self-tolerance, although the former are more abundant and more potent in suppressing autoimmunity. We previously showed that the GITRhighCD25–CD4+ population in normal naive mice gave rise to Foxp3highCD25+CD4+ Treg in vivo; and the latter were suppressive upon in vitro anti-CD3 stimulation (19). It is also known that CD25+CD4+ Treg may lose the expression of CD25, especially when they are subjected to homeostatic proliferation in a T cell-deficient environment (17, 19, 46). It is thus likely that Foxp3-expressing CD25+ and CD25–CD4+ Treg present in normal naive mice are functionally similar and developmentally contiguous, but at different stages of their activation and/or differentiation (9, 47), and that their CD25 phenotype can be convertible in the periphery. The normal thymus also contains both CD25+ and CD25– Treg. Yet, it remains to be determined whether CD25+ and CD25– Treg in the periphery are all produced by the thymus as functionally mature Treg, or peripheral CD25– naive T cells differentiate to CD25+/CD25– Treg under certain in vivo conditions (48, 49, 50, 51).
In conclusion, the degree of reduction of Foxp3-expressing natural Treg, whether they are CD25+ or CD25–, can determine the phenotype and severity of autoimmune/inflammatory disease according to a hierarchical genetic susceptibility of each autoimmune disease (3). High incidences of severe autoimmune diseases, especially T1D and thyroiditis, in IPEX could be attributed to severe deficiency of both CD25+ and CD25– FOXP3+ Treg from the beginning of their ontogeny (5). It is possible that reduction or dysfunction of natural Treg, along with host genetic susceptibility, could be a cause of certain other autoimmune/inflammatory diseases where the etiology is currently unknown. Furthermore, the present results indicate that natural Treg can be exploited for the prevention and treatment of various autoimmune/inflammatory diseases, including autoimmune giant cell myocarditis and resulting dilated cardiomyopathy.
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Acknowledgments |
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Disclosures |
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Footnotes |
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1 This work was supported by grants-in-aid from the Ministry of Education, Sports and Culture of Japan. 
2 Address correspondence and reprint requests to Dr. Shimon Sakaguchi, Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, 53 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan. E-mail address: shimon{at}frontier.kyoto-u.ac.jp
3 Abbreviations used in this paper: Treg, regulatory T cell; IPEX, immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome; T1D, type 1 diabetes; GITR, glucocorticoid-induced TNFR family-related protein; C, complement.
Received for publication December 12, 2005. Accepted for publication January 26, 2006.
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References |
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