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The Journal of Immunology, 2004, 172: 4686-4690.
Copyright © 2004 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: Ligation of the Glucocorticoid-Induced TNF Receptor Enhances Autoreactive CD4+ T Cell Activation and Experimental Autoimmune Encephalomyelitis1

Adam P. Kohm, Julie S. Williams and Stephen D. Miller2

Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The glucocorticoid-induced TNFR (GITR) is expressed at high levels on resting CD4+CD25+ T regulatory (TR) cells and regulates their suppressive phenotype. Accordingly, we show that anti-GITR mAb treatment of SJL mice with proteolipid protein 139–151-induced experimental autoimmune encephalomyelitis significantly exacerbated clinical disease severity and CNS inflammation, and induced elevated levels of Ag-specific T cell proliferation and cytokine production. Interestingly, prior depletion of TR cells failed to result in exacerbated experimental autoimmune encephalomyelitis suggesting alternative targets for the anti-GITR mAb treatment. Importantly, naive CD4+CD25− T cells up-regulated GITR expression in an activation-dependent manner and anti-GITR mAb treatment enhanced the level of CD4+ T cell activation, proliferation, and cytokine production in the absence of TR cells both in vivo and in vitro. Taken together, these findings suggest a dual functional role for GITR as GITR cross-linking both inactivates TR cells and increases CD4+CD25− T cell effector function, thus enhancing T cell immunity.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
One population of T regulatory (TR)3 cells display a mixed phenotype of naive and activated cell surface marker (1), e.g., CD4+CD25+L-selectin (CD62L)high, and inhibit T cell effector function in a TCR-dependent manner. Although the exact mechanism by which TR cells exert their suppressive influence is still unknown, IL-10 production, surface CTLA-4 expression, IL-2 sequestration, costimulatory molecule blockade, and surface/secreted TGF-{beta} expression are all proposed mechanisms by which TR cells may down-regulate effector CD4+ and CD8+ T cell responses (1).

The glucocorticoid-induced TNFR family gene (GITR or TNFRSF18) is a member of the TNF growth factor receptor family that includes CD40, CD27, 4-1BB, and OX40 (2, 3). GITR is predominantly expressed on resting CD4+CD25+ TR cells (4) and functions to regulate TR cell function such that anti-GITR Ab treatment of normal mice exacerbates several models of spontaneous autoimmune disease (4, 5, 6).

In the current study, anti-GITR mAb treatment during the induction phase of experimental autoimmune encephalomyelitis (EAE) significantly enhanced the level of clinical disease severity, CNS inflammation, and autoreactive T cell responses. Importantly, TR cell-depleted CD4+ T cell populations expressed high levels of GITR in an activation-dependent manner and cross-linking of GITR expressed on CD4+CD25− T cells during activation enhanced their level of activation, proliferation, and cytokine production in a concentration-dependent manner suggesting a positive immunoregulatory role for GITR expression on CD4+CD25− T cells.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Mice and materials

SJL female mice, 5- to 6-wk-old, were purchased from Harlan Sprague Dawley (Indianapolis, IN). DO11.10 (OVA323–339/I-Ad-specific) and 5B6 (proteolipid protein (PLP)139–151/I-As-specific) (7) TCR transgenic mice were maintained and bred as previously described (8). The DTA-1 anti-GITR clone was a generous gift of Dr. S. Sakaguchi (Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan).

TR cell depletion

For in vitro depletion, single cell lymph node (LN) suspensions were depleted of TR cell populations by positive selection of CD25+ TR cells using anti-CD25 mAb (7D4), anti-rat {kappa} microbeads (Miltenyi Biotec, Auburn, CA) and an AutoMACs (Miltenyi Biotec). For in vivo depletion, mice received two injections of anti-CD25 mAb (7D4; 500 µg/injection i.p.) on days −4 and −2 before disease initiation. The efficiency of TR cell depletion was determined to be 96–98% effective at the time of disease initiation by immunofluorescence.

Induction and clinical evaluation of PLP139–151-induced EAE

Six- to 7-wk-old female mice were immunized s.c. with 200 µl of an emulsion containing 800 µg of Mycobacterium tuberculosis H37Ra (Difco, Kansas City, MO) and 100 µg of PLP139–151 distributed over three spots on the flank. Individual animals were observed daily and clinical scores were assessed in a blinded fashion on a 0–5 scale as follows: 0 = no abnormality, 1 = limp tail, 2 = limp tail and hind limb weakness, 3 = hind limb paralysis, 4 = hind limb paralysis and forelimb weakness, and 5 = moribund. The data are reported as the mean daily clinical score. Mice were age- and sex-matched for all experiments. In vitro proliferation and ELISPOT assays were performed as previously described (9)

Immunohistochemistry and immunofluorescence

CNS immunohistochemistry was performed as previously described (9). For immunofluorescence, single cell suspensions were washed and incubated with fluorescently tagged Abs directly against a panel of cell surface markers (BD PharMingen, San Diego, CA). Fluorescent staining was analyzed using a LSRII and CellQuest Pro Analysis Software (BD Biosciences, San Jose, CA).

Statistical analysis

Comparisons of clinical scores and ELISPOT frequencies between the various treatment groups were analyzed by unpaired Student’s t test. Values of p < 0.01 were considered significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
We previously reported a functional role for CD4+CD25+ TR cells in regulating the onset and progression of EAE such that TR cell supplementation ameliorated clinical disease severity and CNS inflammation in both active and adoptive EAE (8). To further investigate the protective role of TR cells during EAE, mice were treated with five 1-mg doses of anti-GITR mAb (DTA-1) to inactivate the TR cell population (4, 5) at times spanning the induction and preacute disease phases. Anti-GITR-treated mice displayed a 0% survival rate upon reaching the "onset" phase of clinical disease (Fig. 1A). This was an unexpected result, because the typical survival rate in this EAE system is 100%, suggesting that anti-GITR mAb treatment lethally enhanced the inflammatory response that normally precedes clinical disease onset. However, it was equally possible that the treatment regimen of repeated injections of a high dose of anti-GITR mAb produced a cumulative toxic effect. To test this possibility, similar studies were performed in which mice were immunized with a peptide known to lack inflammatory potential in SJL mice, OVA323–339, in combination with anti-GITR mAb treatments. There was a 100% survival rate in OVA323–339-primed mice receiving the identical anti-GITR mAb treatment regimen (Fig. 1B) suggesting a role for the autoreactive inflammatory response in anti-GITR-treated mice primed with PLP139–151.



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  		FIGURE 1. Anti-GITR Ab treatment exacerbates EAE clinical disease progression and autoreactive T cell effector function. A and B, Effect of high-dose anti-GITR mAb treatment on EAE progression. Mice received five i.p. injections (arrows) of either anti-GITR or rat IgG control Ab (1 mg/injection) on alternating days either (A) beginning with the day of active EAE induction by s.c. injection of PLP139–151/CFA or (B) the day of s.c. injection of OVA323–339/CFA. Data are presented as the daily percent survival and are representative of three separate experiments. C–F, Effect of moderate-low dose anti-GITR mAb treatment on EAE progression. Beginning with the day of active EAE induction by s.c. injection of PLP139–151/CFA, mice received four injections of anti-GITR mAb (100 or 500 µg/injection) on alternating days and were followed for clinical disease (C). D, Effect of anti-GITR mAb treatment on PLP139–151-specific T cell proliferation during EAE. Data are presented as the mean cpm and are representative of three separate experiments. E and F, Effect of anti-GITR mAb on the frequency of PLP139–151-specific Th1 (IFN-{gamma}) and Th2 (IL-4) cells during EAE as measured by ELISPOT. Data are presented the number of PLP139–151-specific IFN-{gamma} (E) and IL-4 (F)-secreting cells per 10 x 105 LN cells. Data presented are representative of three separate experiments. Significant differences from naive (*) or control (**), p < 0.01.

 
In light of the detrimental effect on survival following high dose anti-GITR treatment, similar experiments were performed with a lower dose of anti-GITR mAb. Mice treated with 500 µg of anti-GITR mAb displayed a significantly exacerbated clinical disease severity in the absence of any observed mortality (Fig. 1C). In agreement with clinical disease severity, anti-GITR mAb treatment enhanced the level of PLP139–151-specific T cell proliferation in both the LNs (Fig. 1D) and spleen (data not shown). Anti-GITR mAb treatment also significantly increased the frequency of both PLP139–151-specific Th1- (IFN-{gamma}; Fig. 1E) and Th2- (IL-4; Fig. 1F) cytokine-producing cells, suggesting that anti-GITR mAb treatment functioned to generally enhance the autoantigen-specific immune response during EAE.

It is believed that the clinical symptoms of both EAE and multiple sclerosis manifest as a direct result of CNS inflammation and subsequent myelin damage apparently from the direct and indirect effects of chemokines (10) and proinflammatory cytokines such as IFN-{gamma} and lymphotoxin/TNF{beta} (11, 12). We have previously shown that supplementation of the TR cell population prevents CNS inflammation and ameliorates clinical disease severity potentially via effects on both autoreactive T cell activation and cell trafficking (8). Therefore, we next determined the effect of anti-GITR mAb treatment on the level of CNS inflammation at times corresponding to the peak of the acute clinical disease. In agreement with our previous findings, the level of CNS inflammation correlated with the degree of clinical disease severity such that anti-GITR mAb specifically increased the extent of CD4+ T cell infiltration within the CNS (Fig. 2), without any discernable effects on either the CD8+ or B220+ cell populations which are usually not detected at high levels within the CNS of SJL mice with EAE. Taken together, these findings suggest that anti-GITR mAb treatment enhances autoreactive T cell activation and homing to the CNS resulting in an exacerbated level of clinical disease possibly via the functional inactivation of TR cell populations.



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  		FIGURE 2. Anti-GITR mAb treatment increases CNS inflammation during EAE. Spinal cord tissues from mice, receiving either saline, PLP139–151, or PLP139–151 + anti-GITR mAb (500 µg/injection on days 0, 2, 4, and 6 postimmunization), were examined on days 15–20 post-disease induction for the presence of CD4+, CD8+, and B220+ cells (red). Tissues were also counterstained with 4',6'-diamidino-2-phenylindole (blue). No positive staining was observed in isotype-matched control samples (data not shown); x100 magnification.

 
As previously discussed, anti-GITR mAb treatment is believed to specifically target and block the suppressive function of TR cells (4, 5). Therefore, we reasoned that TR cell depletion before EAE induction should result in enhanced clinical disease severity similar to that seen in mice treated with anti-GITR mAb. To our surprise, TR cell depletion failed to influence the severity of acute clinical disease in our model system (Fig. 3A). In addition, we found that SJL mice depleted of TR cells and subsequently treated with anti-GTIR mAb surrounding PLP139–151/CFA priming displayed enhanced clinical disease (Fig. 3B) suggesting that anti-GITR has direct effects on cells other than CD4+CD25+ TR cells. To further investigate the possibility that the anti-GITR mAb may target additional cell types, we examined the level of GITR expression on CD4+CD25+ and CD4+CD25− T cells. In agreement with previous findings (4), GITR was predominantly expressed on resting CD4+CD25+ T cells with only a small percentage of resting CD4+CD25− T cells expressing detectable levels of the receptor (Fig. 4A). However, GITR expression was rapidly up-regulated on the surface of CD4+CD25− T cells within 24 h of activation by anti-CD3 mAb (Fig. 4B) or following stimulation of naive PLP139–151 TCR transgenic (Tg)+ T cells by Ag (data not shown). Interestingly, the observed up-regulation of GITR expression on CD4+ T cells correlated with their level of CD69 and CD25, both markers of T cell activation, and these experiments have also been repeated using TR cell-depleted cultures (data not shown). To confirm the activation state dependency of GITR expression on CD4+CD25− effector T cells, CD4+CD25− T cells were also stimulated in the presence of F(ab')2 of the anti-CD3 Ab (CD3-F(ab')2) which blocks TCR-induced activation of CD4+ T cells.4 As expected, CD3-F(ab')2 blocked CD4+ T cell activation as determined by CD25, CD54, CD62L, and CD69 expression (data not shown), as well as activation-induced GITR expression (Fig. 4C), indicating that GITR is a phenotypic marker of CD4+ T cell activation.



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  		FIGURE 3. TR cell depletion fails to influence EAE disease progression. A, SJL mice were depleted of TR cells by anti-CD25 mAb injection (500 µg/injection i.p.) on days −4 and −2 before EAE induction by s.c. injection of PLP139–151/CFA. Data are presented as the mean clinical disease score and are representative of three separate experiments. B, SJL mice were depleted of TR cells by anti-CD25 mAb injection (500 µg/injection i.p.) on days −4 and −2 before EAE induction by s.c. injection of PLP139–151/CFA. Mice received four injections of anti-GITR mAb (500 µg/injection) on alternating days and were followed for clinical disease.

 


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  		FIGURE 4. Expression and functional role for GITR in CD4+CD25− effector T cells. A–C, GITR Expression on CD4+CD25− and CD4+CD25+ T cells. A–C, LN cells isolated from naive mice were stained with Abs specific for CD4, CD25, CD62L, and GITR. Some cells were either activated with (B) anti-CD3 Ab (1 µg/106 cells) or (C) anti-CD3 Ab + CD3-F(ab')2 (1 µg/106 cells) for 24 h before immunofluorescence staining. Data are presented as the relative fluorescence intensity of GITR cells. All data are representative of three separate experiments. D–F, Effect of anti-GITR mAb ligation on CD4+CD25− T cell proliferation. D, Naive SJL LN cells were depleted of CD4+CD25+ TR cells before activation with anti-CD3 mAb (0.1 µg/106 cells) in the presence of an increasing concentration of anti-GITR mAb. E, Naive SJL LN cells were depleted of CD4+CD25+ TR cells before activation with increasing concentrations of anti-CD3 mAb in the presence of anti-GITR mAb (1 µg/106 cells). F, LN cells isolated from naive 5B6 PLP139–151 TCR transgenic mice were depleted of CD4+CD25+ TR cells and activated with an increasing concentration of PLP139–151 in the presence of an increasing concentration of anti-GITR mAb. All data are presented as the mean cpm and are representative of three separate experiments.

 
Because both activated CD4+ T cells and TR cells expressed GITR, the possibility existed that anti-GITR mAb treatment may also directly influence CD4+ effector T cell function. To test this, we examined the effects of Ab-mediated cross-linking of GITR on CD4+ T cell proliferation in the absence of TR cells. Activation of TR cell-depleted LN (Fig. 4D) or spleen (data not shown) cells in the presence of anti-GITR mAb increased the level of anti-CD3-induced T cell proliferation in a concentration-dependent manner. Interestingly, anti-GITR mAb treatment produced similar findings when added to TR cell-depleted cultures of naive OVA323–339-specific Tg T cells (DO11.10) activated with suboptimal (0.1 µg/ml), but not optimal, levels of Ag (1 µg/ml) (Fig. 4E). Of direct relevance to the observed effects in our EAE model system, anti-GITR mAb treatment also enhanced the proliferation of TR cell-depleted naive PLP139–151-specific TCR Tg CD4+ T cells in a concentration-dependent manner (Fig. 4F) suggesting that anti-GITR mAb treatment can enhance the effector function of both naive and previously activated CD4+ T cells (Fig. 1D) in the absence of CD4+CD25+ TR cells. Lastly, anti-GITR mAb treatment of TR cell-depleted OVA323–339-specific T cells also enhanced the level of cellular activation as determined by CD54, CD62L, and CD69 expression in a concentration-dependent manner (Fig. 5), but failed to influence CD25 expression.



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  		FIGURE 5. Anti-GITR mAb treatment enhances CD4+CD25− T cell activation. LN cells were isolated from naive DO11.10 TCR transgenic mice and depleted of CD4+CD25+ TR cells before activation in the presence of OVA323–339 (10 µM) and an increasing concentration of anti-GITR mAb for 24 h before determination of the level of CD54, CD62L, CD69, and CD25 surface expression by flow cytometry. Data are presented as the relative fluorescence intensity of each activation marker on CD4+ T cells; MFI, mean fluorescence intensity.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Consistent with previous reports showing that GITR is predominantly expressed on CD4+CD25+ TR cells and that anti-GITR inactivates TR cell functionality (4, 5), we found that treatment of SJL mice with anti-GITR mAb significantly exacerbated PLP139–151-induced clinical EAE, CNS inflammation, and peptide-specific T cell responses (Figs. 1 and 2). However, our present findings also demonstrate that GITR is rapidly up-regulated on naive CD4+CD25− T cells following either mitogen- or Ag-induced T cell activation and that anti-GITR enhanced the level of CD4+ T cell activation, proliferation, and cytokine production in the absence of TR cells in vitro (Figs. 4 and 5). The expression pattern of GITR is thus similar to that of CD25 which is also preferentially expressed at higher levels on resting TR cells, but quickly up-regulated on naive CD4+ T cells upon TCR activation, raising the possibility that CD25 and GITR expression may be regulated by similar mechanisms. Thus, it may be more appropriate to consider GITR expression as a marker of T cell activation rather than defining the TR population.

We previously showed that TR cell supplementation blocked the activation of both naive and previously activated autoreactive CD4+ T cells and protected against the initiation and progression of EAE (8). However, the question remains as to why anti-GITR-mediated TR inactivation (Fig. 1), but not anti-CD25-mediated TR cell depletion, led to enhanced acute clinical EAE (Fig. 3A). One possible explanation may be that the anti-CD25 depletion protocol used in the current studies simply down-regulated the level of CD25 expression on TR cells rather than deplete this population. However, in vitro studies using the same depleting and detecting Ab clones did not result in significant down-regulation of CD25 expression on CD4+ T cells (data not shown). Regardless, the possibility exists that distinct mechanisms may function in vivo and current experiments are closely examining the fate of CD4+CD25+ TR cells following anti-CD25 mAb injection. An alternative explanation for the failure of TR cell depletion to influence the clinical disease progression in EAE may be the existence of redundant compensatory regulatory mechanisms in vivo including other regulatory cell populations. However, further phenotypic and functional characterization of these alternative regulatory populations is necessary to determine their contribution to immune homeostasis during EAE.

Of particular interest is our finding that ligation of GITR by anti-GITR mAb enhanced CD4+ T cell activation, proliferation, and cytokine production in the absence of TR cells both in vivo (Fig. 3B) and in vitro (Fig. 4). Moreover, ligation of GITR appears to optimally augment CD4+ T cell activation in conditions of suboptimal TCR ligation. Therefore, in addition to previously reported effects of anti-GITR on inactivating TR cell activity (4, 5), GITR ligation appears to directly enhance CD4+ T cell effector function by delivering a costimulatory signal thus lowering the signaling threshold of the TCR complex. Collectively, our findings suggest a dual functional role for GITR wherein GITR ligation both inactivates TR cells and, at the same time, increases the activation and effector functions of CD4+CD25− T cells, thus resulting in enhanced T cell-mediated immunity.


   Footnotes
 
1 This work was supported in part by U.S. Public Health Service National Institutes of Health Research Grants NS26543 and NS30871 and National Multiple Sclerosis Society Research Grant RG-A-3489-A-6-1. Back

2 Address correspondence and reprint requests to Dr. Stephen D. Miller, Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, 303 East Chicago Avenue, Chicago, IL 60611. E-mail address: s-d-miller{at}northwestern.edu Back

3 Abbreviations used in this paper: TR, T regulatory; GITR, glucocorticoid-induced TNFR; EAE, experimental autoimmune encephalomyelitis; PLP, proteolipid protein; Tg, transgenic; LN, lymph node; CD62L, L-selectin. Back

4 A. Kohm, J. Williams, A. Bickford, L. Chatenoud, J.-F. Bach, and S. Miller. Treatment with non-mitogenic anti-CD3 mAb induces CD4+ T cell tolerance and functional reversal of established autoimmune disease. Submitted for publication. Back

Received for publication January 8, 2004. Accepted for publication February 24, 2004.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Shevach, E. M.. 2002. CD4+CD25+ suppressor T cells: more questions than answers. Nat. Rev. Immunol. 2:389.[Medline]
  2. Nocentini, G., L. Giunchi, S. Ronchetti, L. T. Krausz, A. Bartoli, R. Moraca, G. Migliorati, C. Riccardi. 1997. A new member of the tumor necrosis factor/nerve growth factor receptor family inhibits T cell receptor-induced apoptosis. Proc. Natl. Acad. Sci. USA 94:6216.[Abstract/Free Full Text]
  3. Gray, P. W., K. Barrett, D. Chantry, M. Turner, M. Feldmann. 1990. Cloning of human tumor necrosis factor (TNF) receptor cDNA and expression of recombinant soluble TNF-binding protein. Proc. Natl. Acad. Sci. USA 87:7380.[Abstract/Free Full Text]
  4. Shimizu, J., S. Yamazaki, T. Takahashi, Y. Ishida, S. Sakaguchi. 2002. Stimulation of CD25+CD4+ regulatory T cells through GITR breaks immunological self-tolerance. Nat. Immunol. 3:135.[Medline]
  5. McHugh, R. S., M. J. Whitters, C. A. Piccirillo, D. A. Young, E. M. Shevach, M. Collins, M. C. Byrne. 2002. CD4+CD25+ immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor. Immunity 16:311.[Medline]
  6. Uraushihara, K., T. Kanai, K. Ko, T. Totsuka, S. Makita, R. Iiyama, T. Nakamura, M. Watanabe. 2003. Regulation of murine inflammatory bowel disease by CD25+ and CD25−CD4+ glucocorticoid-induced TNF receptor family-related gene+ regulatory T cells. J. Immunol. 171:708.[Abstract/Free Full Text]
  7. Waldner, H., M. J. Whitters, R. A. Sobel, M. Collins, V. K. Kuchroo. 2000. Fulminant spontaneous autoimmunity of the central nervous system in mice transgenic for the myelin proteolipid protein-specific T cell receptor. Proc. Natl. Acad. Sci. USA 97:3412.[Abstract/Free Full Text]
  8. Kohm, A. P., P. A. Carpentier, H. A. Anger, S. D. Miller. 2002. Cutting edge: CD4+CD25+ regulatory T cells suppress antigen-specific autoreactive immune responses and central nervous system inflammation during active experimental autoimmune encephalomyelitis. J. Immunol. 169:4712.[Abstract/Free Full Text]
  9. Tompkins, S. M., J. Padilla, M. C. Dal Canto, J. P. Ting, L. Van Kaer, S. D. Miller. 2002. De novo central nervous system processing of myelin antigen is required for the initiation of experimental autoimmune encephalomyelitis. J. Immunol. 168:4173.[Abstract/Free Full Text]
  10. Karpus, W. J., N. W. Lukacs, B. L. McRae, R. M. Streiter, S. L. Kunkel, S. D. Miller. 1995. An important role for the chemokine macrophage inflammatory protein-1{alpha} in the pathogenesis of the T cell-mediated autoimmune disease, experimental autoimmune encephalomyelitis. J. Immunol. 155:5003.[Abstract]
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