By
From the Institut National de la Sante et de la Recherche Medicale U28, Institut Fédératif de Recherche 30, Université Paul Sabatier, 31059 Toulouse, France
Autoreactive anti-MHC class II T cells are found in Brown Norway (BN) and Lewis (LEW)
rats that receive either HgCl2 or gold salts. These T cells have a T helper cell 2 (Th2) phenotype in the former strain and are responsible for Th2-mediated autoimmunity. In contrast,
T cells that expand in LEW rats produce IL-2 and prevent experimental autoimmune encephalomyelitis, a cell-mediated autoimmune disease. The aim of this work was to investigate, using T cell lines derived from HgCl2-injected LEW rats (LEWHg), the effect of these autoreactive
T cells on the development of Th2-mediated autoimmunity. The five LEWHg T cell lines obtained protect against Th2-mediated autoimmunity induced by HgCl2 in (LEW × BN)F1 hybrids. The lines produce, in addition to IL-2, IFN- and TGF-
, and the protective effect is
TGF-
dependent since protection is abrogated by anti-TGF-
treatment. These results identify regulatory, TGF-
-producing, autoreactive T cells that are distinct from classical Th1 or
Th2 and inhibit both Th1- and Th2-mediated autoimmune diseases.
Mercuric chloride or gold salts induce in Brown Norway (BN)1, in (Lewis [LEW] × BN)F1 hybrids, and
in susceptible mice, a transient Th2-dependent B cell polyclonal activation (1) responsible for an increase in serum
IgE concentration and for the production of various autoantibodies including anti-DNA and antilaminin antibodies (for review see reference 1). These latter antibodies are
associated with the occurrence of an autoimmune glomerulonephritis as observed in some patients treated with gold
salts (5). T cells that recognize either self-MHC class II
molecules or an ubiquitous self-peptide presented by MHC
class II molecules play an important role in the induction of
B cell polyclonal activation in this model (6, 7). In contrast,
HgCl2 provokes in LEW rats, a nonantigen-specific suppression and protects from autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE) to which this
strain is otherwise highly susceptible. Autoreactive anti-self- MHC class II T cells have also been detected in HgCl2-
injected LEW rats (8). Autoreactive T cell lines have been
derived from gold-injected BN rats and HgCl2-injected
LEW rats (LEWHg T cell lines) by repeated stimulations
with syngeneic APCs. In both strains, these anti-MHC class
II T cell lines are RT1.B- (mouse IA equivalent), but not
RT1.D- (mouse IE equivalent) restricted (7, 8). Whereas T
cell lines derived from BN rats produce IL-4 and are able to
passively transfer autoimmunity into CD8-depleted naive BN rats (7), the LEWHgA T cell line, derived from
HgCl2-injected LEW rats, produces IL-2 and IFN- The aim of this study was to assess the effect of adoptive
transfer of LEWHg T cell lines on the course of Th2mediated autoimmunity induced by HgCl2 in (LEW × BN)F1 hybrids. We show that (a) the lines produce TGF- Rats
BN and LEW rats were obtained from Charles River (Rouen,
France) and maintained in our facilities. F1 hybrids were obtained by crossing BN male and LEW female rats in our animal house.
8-12-wk-old males or females were used in the experiments.
Culture Medium
RPMI 1640 (Biochrom KG, Berlin, Germany) was supplemented with streptomycin (100 µg/ml) and penicillin (100 U/ml),
nonessential amino acids (0.1 mM), L-glutamine (2 mM; GIBCO,
Paisley, U.K.), sodium pyruvate (1 mM; Biochrom KG), and 2-ME
(5 × 10 mAbs and FACS® Analysis
R73, W3/25, OX8, OX81, and B10.H2 mAbs are mouse
IgG1 mAbs that recognize rat TCR- The phenotype of cells was determined by double staining;
cells were incubated with FITC-labeled W3/25 and biotinylatedOX8 mAb, and then streptavidin-phycoerythrin (Sigma Chemical Co.) was added. The cells were analyzed with a Coulter Epics
XL (Coultronics, Margency, France); a minimum of 5,000 cells
were counted.
T Cell Lines
The five LEWHg T cell lines (LEWHg A, B, C, D, and E)
used in this study have been previously described (8). They were derived from lymph node cells of five distinct LEW rats injected with HgCl2 for 7 d; they are CD4+CD8 Cytokine Assays
T cell lines were stimulated with irradiated thymocytes as described above, in the absence of Con A supernatant; 24-, 48-, 72-, 96-, and 120-h culture supernatants were collected and stored at
TGF- Experimental Design
HgCl2 Injections and Follow Up of Mercury Disease.
Rats were injected with HgCl2 (100 µg/100 g body wt, subcutaneously, 3 times/wk) during 4 to 6 wk (6). All the rats were bled once a
week for determination of serum IgE concentration, antilaminin,
and occasionally, anti-DNA antibody titers as previously described (17, 18). Kidneys were processed at the time of killing for
immunofluorescence studies, using FITC-conjugated sheep anti-
rat IgG antiserum as previously described (7). The intensity of
fluorescence was scored on a scale from 0 to 4 in blind study by
two independent examiners.
Adoptive Transfer of T Cell Lines.
T cell lines (LEWHgA, LEWHgB,
LEWHgC, LEWHgD, and LEWHgE) were stimulated for 3 d
with syngeneic irradiated thymocytes only or LEWOVA with
syngeneic irradiated thymocytes plus ovalbumin. T cell lines (107
cells) were then intraperitoneally injected into naive F1 rats 2 wk
before the first HgCl2 injection.
Thymectomy, Anti-CD8, and Anti-TGF- Statistical Analysis
Serum IgE concentration, antilaminin, and anti-DNA antibody titers were compared between the different groups by using
nonparametrical tests. The number of rats per group with kidneybound IgG was compared by chi-square analysis.
As previously described (8),
the five LEWHg T cell lines used in this study are CD4+
CD8 Table 1.
Cytokines Produced by the LEWHg and LEWOVA
T Cell Lines
and
protects LEW rats against EAE, a Th1-mediated autoimmune disease, by inducing regulatory CD8+ T cells (8).
in addition to IL-2 and IFN-
, (b) adoptive transfer of the
lines prevents HgCl2-induced autoimmunity, and (c) this
protection is abrogated after anti-TGF-
mAb administration.
5 M); Sigma Chemical Co., St. Louis, MO).
/
chains (9), CD4 (10),
CD8 (11), rat IL-4 (12), and thyroglobulin, respectively. The
IgG1 1D11.16 and the IgG2a 2G.7 anti-TGF-
mAbs were provided by Dr. W. Waegell (Celtrix Pharmaceuticals, Santa Clara,
CA; 13) and by Dr. C.M. Melief (University of Leiden, Leiden,
Netherlands; 14), respectively. The IgG1 DB.1 and DB.12 antiIFN-
mAbs were provided by Dr. P.H. Van der Meide (15) and
B10.H2 mAb by Dr. D. Glotz (Paris, France). The W3/25 and
OX8 hybridomas were obtained from the Public Health Laboratory Service (Oxford, U.K.); Dr. T. Hunig (Würzburg, Germany), and Dr. D. Mason (Medical Research Council, Oxford,
U.K.) provided the R73 and OX81 hybridomas, respectively. Ascites and purified antibodies were prepared as described (16).
TCR-
/
+, proliferate
in the presence of syngeneic APCs, and are MHC class II
(RT1.B)-restricted. The LEWOVA T cell line was also a CD4+
CD8
TCR-
/
+ T cell line derived from the draining lymph
nodes of a LEW rat immunized 10 d before with 100 µg OVA in
CFA. Except when otherwise mentioned, T cell lines were stimulated repeatedly every 2 wk as follows: 2 × 105 cells/well were
cultured in 24-well flat-bottomed plates (Nunc, Kamstrup, Denmark), in a 6% CO2 incubator in the presence of normal irradiated (3,000 rads) syngeneic thymocytes (5-10 × 106/well), in a
volume of 1 ml/well culture medium supplemented with 10% heatinactivated FCS and 10% Con A supernatant (8). The LEWOVA
T cell line was stimulated with 50 µg/ml OVA (Sigma Chemical Co.).
20°C. IL-2 production was assessed using proliferation of the
IL-2-dependent CTLL-2 cell line (7). IFN-
production was determined by two-site sandwich ELISA (7). Values were expressed as U/ml IFN-
referring to a standard curve constructed
using serial dilutions of recombinant purified rat IFN-
(a gift
from Dr. P. van der Meide, Vrije Universiteit, Amsterdam, Netherlands). IL-4 detection was based upon the ability of this cytokine to upregulate MHC class II molecule expression on B cells
(12). The assay was performed, in the presence or in the absence
of the OX81 anti-rat IL-4 mAb (50 µg/ml), by fluorocytometry.
Recombinant rat IL-4, (provided by Dr. D. Mason, Medical Research Council, CIU, Oxford, U.K.) was used as a positive control.
was measured by ELISA (R&D Sys., Inc., Abingdon,
U.K.) according to the manufacturer's instructions. To demonstrate that TGF-
was produced by T cells and not by APCs, the
LEWHgA T cell line was also stimulated as follows: 96 flat-bottomed well plates were precoated with rabbit anti-mouse Ig antibodies (DAKOPATTS, Copenhagen, Denmark) overnight; the
LEWHgA T cell line was then added (5 × 104/well), together
with mouse anti-rat TCR-
/
mAb (50 µg/ml) as described
elsewhere (9). Supernatant was collected after 24, 48, and 96 h.
Cells were also cultured for 72 h to assess the proliferative response. The anti-rat TCR-
/
mAb was replaced in control cultures by the B10.H2 mAb.
Treatment.
Rats were
thymectomized at 8 wk of age (19), allowed to recover for 3 wk, and then injected with the LEWHgA T cell line; 15 d later,
rats were injected with HgCl2. In addition, some rats received the
anti-CD8 (OX8) mAb or the control isotype-matched B10.H2
mAb (500 µg intraperitoneally, once a week for 1 mo) from the
first HgCl2 injection (8). The effect of TGF-
neutralization was
assessed using the anti-TGF-
mAbs 1D11.16 or 2G.7 (2 mg intraperitoneally on days
2, 0, 3, 6, and 9 with respect to the first
HgCl2 injection).
Description of T Cell Lines.
TCR-
/
+ and proliferate in the presence of normal syngeneic MHC class II+ APCs. They all produced IL-2
and IFN-
(Table 1) with a peak at 24 h for IL-2 and 48 or 72 h for IFN-
. The LEWHg, but not the LEWOVA,
T cell lines produced TGF-
(Table 1) with a peak at 96 or
120 h of stimulation. None of these cytokines were detected in supernatants from irradiated APCs only, or in supernatants of resting T cell lines (Table 1). To eliminate a
role for APCs in producing TGF-
, the LEWHgA T cell
line was stimulated by plate-bound anti-TCR mAb in the
absence of APCs. In such conditions, the LEWHgA T cell
line proliferated (index 3 ± 0.5) and produced TGF-
(1.72 ± 0.05 ng/ml). No proliferation and no TGF-
secretion were observed when the anti-TCR mAb was replaced by the control B10.H2 mAb.
Line (No. of exp.)
IL-2*
IFN-
TGF-
cpm × 10
3
U/ml
ng/ml
LEWHgA (8)
12 ± 3.5
15 ± 9
2.3 ± 0.9
LEWHgB (2)
8, 6
10, 13
1.7, 0.9
LEWHgC (2)
14, 7
21, 9
0.45, 0.39
LEWHgD (2)
8, 12
2, 4.5
0.15, 0.3
LEWHgE (2)
9.6, 15
13, 15
0.6, 0.5
LEW OVA (5)
10.5 ± 1.5
12 ± 3
<0.1
Unstimulated lines
0.5 ± 0.1
0
<0.1
Results are expressed as mean ± SD when five or eight experiments
were performed; otherwise individual values were given.
*
The background value of CTLL-2 cells was 700 ± 150 cpm.
The supernatant from the stimulated LEWHgB T cell line increased MHC class II expression on B cells (mean fluorescence intensity of 51 versus 10 for B cells cultured alone), and this increase was abolished by addition of the anti-IL-4 OX81 mAb (mean fluorescence intensity of 14) suggesting that this line produced IL-4. None of the other LEWHg or LEWOVA T cell lines produced detectable amounts of IL-4 in this assay (not shown).
Anti-MHC Class II LEWHg T Cell Lines Prevent HgCl2induced Autoimmunity in F1 RatsTransfer of the LEWHgA
T cell line at the time of the first HgCl2 injection attenuated the autoimmune manifestations, but did not completely prevent the polyclonal activation of B cells nor renal
IgG deposition (data not shown). By contrast, HgCl2-induced immunopathological manifestations were abrogated or considerably reduced in rats that received the LEWHg T cell
lines 15 d before the first HgCl2 injection. In these rats, antilaminin antibody titer was much lower as compared to
that of HgCl2-injected rats (P <0.005) and did not differ
from that observed in normal rats (Fig. 1, A and B). Similar
results were obtained concerning anti-DNA antibodies (not
shown). Serum IgE concentration dramatically decreased when compared to HgCl2-injected rats (P <0.01), but remained higher than in normal rats (Fig. 1, C and D). The
number of rats with glomerular IgG deposits was reduced
in those who received the LEWHg T cell lines (from 66 to
19% depending upon the line, versus 100% in rats that received HgCl2 only; P <0.01); when considering rats that
still exhibited IgG glomerular deposits, the intensity of immunofluorescence was greatly diminished when compared
to rats injected with HgCl2 only (Fig. 2). Transfer of the
LEWOVA T cell line had no effect on HgCl2-induced autoimmunity; these rats behaved as rats injected with HgCl2
only with respect to serum IgE concentration, antilaminin
antibody titer (Fig. 1, A and C), and glomerular IgG deposits (Fig. 2).
CD8+ Cells and Recent Thymic Emigrants Are Not Involved in the Protection.
Since we had previously observed that
the LEWHgA T cell line protects from EAE in a CD8-dependent manner (8), the potential role of CD8+ cells was addressed in the present model. To achieve CD8+ cell depletion, rats were thymectomized and injected with the anti-CD8 mAb. These rats displayed <1.5% CD8+ cells in
spleen and lymph nodes at the time of killing, compared to
15 ± 3% in control rats. In these rats, HgCl2 injections induced similar, or even more severe, manifestations than in
control rats injected with HgCl2 (Fig. 3, A and B). Transfer
of the LEWHgA T cell line inhibited HgCl2-induced antilaminin antibody production (Fig. 3 A), increase in serum
IgE concentration (Fig. 3 B), and glomerular IgG deposits
(not shown) whether rats were thymectomized and treated
with the anti-CD8 mAb or not. These results show that neither CD8+ cells nor recent thymic emigrants were involved in the protection.
Protection of Mercury-induced Autoimmunity by LEWHg CD4+ T Cell Lines Is TGF-
We next examined whether the inhibition of mercury disease induced by
transfer of LEWHg T cell lines depends on the production of TGF- in vivo. Interestingly, blocking TGF-
by administration of 1D11-16 mAb at the time of mercury disease induction completely abrogated the LEWHgA-mediated protective effect (Fig. 4). This is exemplified by the
restoration of autoantibody production (Fig. 4 A), IgE synthesis (Fig. 4 B), and the reappearance of kidney Ig deposits
to levels comparable to those observed in HgCl2-injected control rats (not shown). Administration of a different
TGF-
-specific mAb (2G.7) also prevented the protection
induced by the transfer of LEWHgA T cells (Table 2).
Treatment with anti-TGF-
mAb alone did not influence
HgCl2-induced autoimmune syndrome.
|
To demonstrate that TGF--dependent inhibition of
Th2-mediated autoimmunity is not a unique property of
LEWHgA T cell line, we tested the effect of anti-TGF-
mAb administration on the protection induced by the
LEWHgA and two other self-MHC class II reactive T cell
lines. LEWHgA, LEWHgB, and LEWHgC T cell lines have
a comparable regulatory potential when transferred to F1
rats before induction of HgCl2-induced disease (Table 2).
Administration of the anti-TGF-
2G.7 mAb at the time
of disease induction completely reverted the protective effect induced by the transfer of LEWHg T cell lines as
shown by the complete restoration of the disease criteria including loss of body weight (Table 2).
Taken together our data show that three autoreactive
anti-self-MHC class II T cell lines independently derived
from HgCl2-injected LEW rats prevent Th2-mediated autoimmune disorders in (LEW × BN)F1 rats, and that their
strong immunoregulatory potential is dependent on the
production of TGF-.
This study shows that five autoreactive anti-self-MHC
class II T cell lines derived from distinct HgCl2-injected
LEW rats protect susceptible (LEW × BN)F1 rats from
HgCl2-induced, Th2-mediated autoimmunity. These lines
produce TGF- that is responsible for the protection observed.
An increase in serum IgE concentration, although considerably less than in controls, persisted in HgCl2-injected rats transferred with the LEWHg T cell lines. This was possibly due to the recently described direct effect of HgCl2 on IL-4 gene transcription (20).
Autoreactive anti-MHC class II T cells that may enhance or suppress immune responses have been described in normal situations and are responsible for the autologous mixed lymphocyte reaction (see review in reference 21). Similar cells may also participate in the peripheral control of pathogenic autoreactive T cells. Thus, autoreactive anti-MHC class II T cell lines derived either from diabetic biobreeding rats, or from nondiabetic NOD mice prevent autoimmune diabetes when transferred to diabetes-prone biobreeding rats (22) or NOD mice (23), respectively. HgCl2 has been recently shown to induce a polyclonal activation of T cells in both BN and LEW rats (24), and thus, probably allows, among other T cells, the expansion of autoreactive antiself-MHC class II T cells, from precursors present in normal animals (25).
The mechanism of action of these autoreactive, regulatory T cells is not yet completely understood. We will first
discuss the role of cytokines and then the nature of cells involved in protection. Our results show that protection is
provided by TGF-. We cannot rule out that other cytokines produced by these lines also play a role in the regulation observed, but neutralization of TGF-
alone abrogated the regulatory effect of the line indicating that this
cytokine was of major importance. The regulatory T cell lines described in other systems (26) were not tested for
their ability to produce TGF-
, except for those derived
from animals orally tolerized with myelin basic protein that
were able to prevent EAE in a TGF-
-dependent manner
(27). However, there is now large evidence that TGF-
plays a major role in controlling the emergence of several
autoimmune or inflammatory diseases (30).
A second point to be discussed concerns the nature of
the cells involved in the protection. One possibility is that
the T cell lines are responsible by themselves for the effect
through TGF- production. Powrie and co-workers have
shown that autoaggressive and regulatory T cells coexist in
normal rats and mice (40, 41). The autoaggressive Th1-like
subset induces severe immunopathological manifestations,
such as colitis in mice, when transferred into immunocompromised recipients. The regulatory Th2-like subset, by contrast, has no pathogenic effect and, in addition, prevents manifestations induced by the former subset. Powrie et al.
have shown in mice that this protection was due to TGF-
,
and not to IL-4 (42). The LEWHg T cell lines might belong to this regulatory subset, but interestingly, do not have
a Th2-like phenotype since they produce IL-2 and IFN-
but no detectable IL-4 with a biological assay except for
one T cell line. Taken together, these results identify selfreactive T cells producing, in addition to TGF-
, either
Th1- or Th2-associated cytokines, with a strong regulatory potential in both Th1- and Th2-mediated autoimmune
diseases. Another nonexclusive possibility is that the T cell
line recruits other T cells that participate in protection. In
this respect, CD8+ T cells are crucial in the protective effect
of the LEWHgA CD4+ T cell line towards EAE in LEW
rats (8). CD8+ cells play no role in the protection of F1 rats
from HgCl2-induced autoimmunity since protection was
still observed in rats profoundly depleted of CD8+ cells after thymectomy and anti-CD8 mAb treatment. The difference in CD8+ cell requirement in both situations could be
due to the different genetic make up of the recipients or to
differences in experimental models. That the LEWHgA T
cell line had to be injected 2 wk before the first HgCl2 injection is compatible with a recruitment of CD4+ cells by
the T cell line. If recruited cells play a role in protection against HgCl2-induced autoimmunity, they could resemble
three previously described regulatory T cell populations. (a)
The first possiblity is recent thymic emigrants, CD4+, or
CD8+ T cells that have been converted into regulatory cells
by the autoreactive T cells selected on thymic epithelium in
an IL-4-independent manner (43). It is unlikely that recruited recent thymic emigrant cells were at play in our
model since thymectomized rats injected 3 wk later with
the LEWHgA T cell line and injected with HgCl2 were
still protected. (b) The recruited T cells could be similar to the antiidiotypic or antiergotypic T cells described by
Lohse et al. (44). (c) They could also be related to regulatory cells guided to tolerance in the so-called infectious tolerance model (45). These hypotheses are currently being
tested.
To conclude, the fact that HgCl2 can induce the expansion, among other T cells, of a subset of regulatory T cells
that may recognize ubiquitous peptides in the context of
MHC class II molecules is probably of importance for our
understanding of the regulatory circuits involved in autoimmunity. Depending upon the strain tested, those T cells
could produce different cytokines: self MHC class II-reactive T cells developing in BN rats produce IL-4 and induce Th2-mediated disorders, whereas T cells expanding in LEW
rats preferentially produce TGF- responsible for downregulation of autoimmunity.
Address correspondence to Dr. L. Pelletier, INSERM U28, Hôpital Purpan, Place du Dr. Baylac, 31059 Toulouse Cedex, France.
Received for publication 1 August 1996 and in revised form 10 March 1997.
1 Abbreviations used in this paper: AU, arbitrary units; BN, Brown Norway; EAE, experimental autoimmune encephalomyelitis; LEW, Lewis; LEWHg, HgCl2-injected LEW rats.We acknowledge Drs. H. Groux and J.C. Guéry for helpful discussion, Celtrix Pharmaceuticals Inc. and Dr.
C.M. Melief for providing anti-TGF- mAbs, M. Calise for her excellent technical assistance, and Dr. L. Chatenoud for providing purified 2G.7 antibody.
This work was supported in part by a grant from the European Community Biotech program BIO-CT920316. A. Badou is supported by the Association pour la Recherche sur le Cancer. A. Saoudi is supported by the Centre National de la Recherche Scientifique.
1. | Goldman, M., P. Druet, and E. Gleichmann. 1991. TH2 cells in systemic autoimmunity: insights from allogeneic diseases and chemically-induced autoimmunity. Immunol. Today. 12: 223-227 [Medline]. |
2. | Mathieson, P.W., S. Thiru, and D.B.G. Oliveira. 1993. Regulatory role of OX22high T cells in mercury-induced autoimmunity in the Brown Norway rat. J. Exp. Med. 177: 1309-1316 [Abstract]. |
3. | Gillespie, K.M., F.J. Qasim, L.M. Tibbats, S. Thiru, D.B.G. Oliveira, and P.W. Mathieson. 1995. Interleukin-4 gene expression in mercury-induced autoimmunity. Scand. J. Immunol. 41: 268-272 [Medline]. |
4. | Biancone, L., G. Andres, H. Ahn, A. Lim, C. Dai, R. Noelle, H. Yagita, C. De Martino, and I. Stamenkovic. 1996. Distinct regulatory roles of lymphocyte costimulatory pathways on T helper type 2-mediated autoimmune disease. J. Exp. Med. 183: 1473-1482 [Abstract]. |
5. | Fillastre, J.P., P. Druet, and J.P. Mery. 1988. Proteinuric nephropathies associated with drugs and substances of abuse. In The Nephrotic Syndrome. J.S. Cameron and R.J. Glassock, editors. Marcel Dekker, New York. 697-744. |
6. | Rossert, J., L. Pelletier, R. Pasquier, and P. Druet. 1988. Autoreactive T cells in mercury-induced autoimmunity. Demonstration by limiting dilution analysis. Eur. J. Immunol. 18: 1761-1766 [Medline]. |
7. | Saoudi, A., M. Castedo, D. Nochy, C. Mandet, R. Pasquier, P. Druet, and L. Pelletier. 1995. Self reactive anti-class II Th2 cell lines derived from gold salt-injected rats trigger B cell polyclonal activation and transfer autoimmunity in CD8depleted normal syngeneic recipients. Eur. J. Immunol. 25: 1972-1979 [Medline]. |
8. | Castedo, M., L. Pelletier, J. Rossert, R. Pasquier, H. Villarroya, and P. Druet. 1993. Mercury-induced autoreactive anti-class II T cell line protects from experimental autoimmune encephalomyelitis by the bias of CD8+ antiergotypic cells in Lewis rats. J. Exp. Med. 177: 881-889 [Abstract]. |
9. | Hunig, T., H.-J. Wallny, J.K. Hartley, A. Lawetzky, and G. Tiefenthaler. 1989. A monoclonal antibody to a constant determinant of the rat T cell antigen receptor that induces T cell activation. Differential reactivity with subsets of immature and mature T lymphocytes. J. Exp. Med. 169: 73-86 [Abstract]. |
10. | Williams, A.F., G. Galfré, and C. Milstein. 1977. Analysis of cell surface by xenogeneic myeloma-hybrid antibodies: differentiation antigens of rat lymphocytes. Cell. 12: 663-673 [Medline]. |
11. | Brideau, R.J., P.B. Carter, W.R. Mc, Master, D.W. Mason, and A.F. Williams. 1980. Two subsets of rat T lymphocytes defined with monoclonal antibodies. Eur. J. Immunol. 10: 609-615 [Medline]. |
12. | Ramirez, F., D.J. Fowell, M. Puklavec, S. Simmonds, and D. Mason. 1996. Glucocorticoids promote a Th2 cytokine response by CD4+ T cells in vitro. J. Immunol. 156: 2406-2412 [Abstract]. |
13. |
Dasch, J.R.,
D.R. Pace,
W. Waegell,
D. Inenaga, and
L. Ellingsworth.
1989.
Monoclonal antibodies recognizing transforming growth factor-![]() ![]() |
14. |
Lucas, C.,
L.N. Bald,
B.M. Fendly,
M. Mora-Worms,
I.S. Figari,
E.J. Patzer, and
M.A. Palladino.
1990.
The autocrine
production of transforming growth factor-![]() |
15. | van der Meide, P.H., A.H. Borman, H.G. Beljaars, M.A. Dubbeld, C.A.D. Botman, and H. Schellekens. 1989. Isolation and characterization of monoclonal antibodies directed to rat interferon-gamma. Lymphokine Res. 8: 439-449 [Medline]. |
16. | Pelletier, L., J. Rossert, R. Pasquier, M.C. Vial, and P. Druet. 1990. Role of CD8+ T cells in mercury-induced autoimmunity or immunosuppression in the rat. Scand. J. Immunol. 31: 65-74 [Medline]. |
17. |
Pelletier, L.,
R. Pasquier,
J. Rossert,
M.-C. Vial,
C. Mandet, and
P. Druet.
1988.
Autoreactive T cells in mercury-induced
autoimmunity. Ability to induce the autoimmune disease.
J.
Immunol.
140:
750-754
|
18. | Dubey, C., J. Kuhn, M.C. Vial, P. Druet, and B. Bellon. 1993. Anti-interleukin-2 receptor monoclonal antibody therapy supports a role for Th1-like cells in HgCl2-induced autoimmunity in rats. Scand. J. Immunol. 37: 406-412 [Medline]. |
19. | Sedgwick, J.D.. 1988. Long-term depletion of CD8+ T cells in vivo in the rat: no observed role for CD8+ (cytotoxic/ suppressor) cells in the immunoregulation of experimental allergic encephalomyelitis. Eur. J. Immunol. 18: 495-502 [Medline]. |
20. | Prigent, P., A. Saoudi, C. Pannetier, P. Graber, Y. Bonnefoy, P. Druet, and F. Hirsch. 1995. Mercuric chloride, a chemical responsible for Th2-mediated autoimmunity in Brown-Norway rats, directly triggers T cells to produce IL-4. J. Clin. Invest. 96: 1484-1489 [Medline]. |
21. | Zauderer, M.. 1989. Origin and significance of autoreactive T cells. Adv. Immunol. 45: 417-437 [Medline]. |
22. |
Nagata, M., and
J.-W. Yoon.
1994.
Prevention of autoimmune type I diabetes in biobreeding (BB) rats by a newly established, autoreactive T cell line from acutely diabetic BB
rats.
J. Immunol.
153:
3775-3783
|
23. | Reich, E.-P., D. Scaringe, J. Yagi, S. Sherwin, and C.A. Janeway. 1989. Prevention of diabetes in NOD mice by injection of autoreactive T-lymphocytes. Diabetes. 38: 1647-1651 [Abstract]. |
24. |
Fillon, J.,
R. Baccala,
J. Kuhn,
P. Druet, and
B. Bellon.
1997.
Evidence for heterogeneous TCRV![]() |
25. |
Agrawal, B.,
M. Manickasundari,
E. Fraga, and
B. Singh.
1991.
T cells that recognize peptide sequences of self MHC
class II molecules exist in syngeneic mice.
J. Immunol.
147:
383-390
|
26. | Saoudi, A., B. Seddon, V. Heath, D. Fowell, and D. Mason. 1996. The physiological role of regulatory T cells in the prevention of autoimmunity: the function of the thymus in the generation of the regulatory T cell subset. Immunol. Rev. 149: 196-216 . |
27. | Chen, Y., V.K. Kuchroo, J.-I. Inobe, D.A. Hafler, and H.L. Weiner. 1994. Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. Science (Wash. DC). 265: 1237-1240 [Medline]. |
28. |
Santos, L.M.B.,
A. Al-Sabbagh,
A. Londono, and
H. Weiner.
1994.
Oral tolerance to myelin basic protein induces regulatory TGF-![]() |
29. | Chen, Y., J.-I. Inobe, and H.L. Weiner. 1995. Induction of oral tolerance to myelin basic protein in CD8-depleted mice: both CD4+ and CD8+ cells mediate active suppression. J. Immunol. 155: 910-916 [Abstract]. |
30. |
Wahl, S.M..
1994.
Transforming growth factor ![]() |
31. |
Kuruvilla, A.P.,
R. Shah,
G.M. Hochwald,
H.D. Liggitt,
M.A. Palladino, and
G.J. Thorbecke.
1991.
Protective effect
of transforming growth factor ![]() |
32. |
Santambrogio, L.,
G.M. Hochwald,
B. Saxena,
C.-H. Leu,
J.E. Martz,
J.A. Carlino,
N.H. Ruddle,
M.A. Palladino,
L.I. Gold, and
J. Thorbecke.
1993.
Studies on the mechanisms by
which transforming growth factor-![]() ![]() |
33. |
Jung, S.,
H.J. Schluesener,
B. Schmidt,
A. Fontana,
K.V. Toyka, and
H.-P. Hartung.
1994.
Therapeutic effect of transforming growth factor-![]() |
34. |
Wahl, S.M.,
J.B. Allen,
G.L. Costa,
H.L. Wong, and
J.R. Dasch.
1993.
Reversal of acute and chronic synovial inflammation by anti-transforming growth factor ![]() |
35. |
Meyers, C.M., and
C.J. Kelly.
1994.
Immunoregulation and
TGF-![]() |
36. |
Neurath, M.F.,
I. Fuss,
B.L. Kelsall,
D.H. Presky,
W. Waegell, and
S. Strober.
1996.
Experimental granulomatous colitis in mice is abrogated by induction of TGF-![]() |
37. |
Shull, M.M.,
I. Ormsby,
A.B. Kier,
S. Pawlowski,
R.J. Diebold,
M. Yin,
R. Allen,
C. Sidman,
G. Proetzel,
D. Calvin, et al
.
1992.
Targeted disruption of the mouse transforming
growth factor-![]() |
38. |
Christ, M.,
N.L. McCartney-Francis,
A.B. Kulkarni,
J.M. Ward,
D.E. Mizel,
C.L. Mackall,
R.E. Gress,
K.L. Hines,
H. Tian,
S. Karlsson, et al
.
1994.
Immune dysregulation in TGF![]() |
39. |
Dang, H.,
A.G. Geiser,
J.J. Letterio,
T. Nakabayashi,
L. Kong,
G. Fernandes, and
N. Talal.
1995.
SLE-like autoantibodies and Sjögren's syndrome-like lymphoproliferation in
TGF-![]() |
40. | Powrie, F., and D. Mason. 1990. OX-22high CD4+ T cells induce wasting disease with multiple organ pathology: prevention by the OX-22low subset. J. Exp. Med. 172: 1701-1708 [Abstract]. |
41. | Powrie, F., M.W. Leach, S. Mauze, S. Menon, L.B. Caddle, and R.L. Coffman. 1994. Inhibition of Th1 responses prevents inflammatory bowel disease in scid mice reconstituted with CD45RBhi CD4+ T cells. Immunity. 1: 553-582 [Medline]. |
42. |
Powrie, F.,
J. Carlino,
M.W. Leach,
S. Mauze, and
R.L. Coffman.
1996.
A critical role for transforming growth factor-![]() |
43. | Modigliani, Y., A. Bandeira, and A. Coutinho. 1996. A model for developmentally acquired thymus-dependent tolerance to central and peripheral antigens. Immunol. Rev. 149: 156-174 . |
44. | Lohse, A., and I.R. Cohen. 1992. Immunoregulation: studies of physiological and therapeutic autoreactivity by T cell vaccination. Springer Semin. Immunopathol. 14: 179-186 [Medline]. |
45. | Cobbold, S.P., E. Adams, S.E. Marshall, J.D. Davies, and H. Waldmann. 1996. Mechanisms of peripheral tolerance and suppression induced by monoclonal antibodies to CD4 and CD8. Immunol. Rev. 149: 5-33 [Medline]. |