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*
Department of Immunology, Imperial College School of Medicine, and
Medical Research Council Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital, London, United Kingdom
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Given that the role of cytokines in the maintenance of transplantation tolerance is less than clear, we have explored an alternative possibility, namely that anergic T cells exert regulatory functions by a cytokine-independent mechanism. Their inhibitory properties were first demonstrated in a human in vitro system (7, 8), and have been reproduced using mouse cells (9). In addition, we have reported that anergic donor-specific T cells can prolong the survival of skin allografts in vivo (10). Related phenomena have been reported by other groups in human (11) and murine systems (12, 13).
In this study we have examined the mechanisms whereby anergic T cells inhibit responsive T cells, and have focused our attention on the possibility that their inhibitory effects are mediated through the regulation of APC function.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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NODasp transgenic mice expressing a mutant MHC class II molecule (H2-Abg7, Ser57 to Asp) have been previously described (14). They were bred at the Biological Services Unit of the Imperial College School of Medicine. Male C57BL/10 mice were purchased from Olac Harlan (Bicester, U.K.). TCR-transgenic DO.11.10 mice were kindly provided by Drs. D. Gray and H. Reiser at our department.
T cell clones
2E4 and 1F8 are alloreactive (NOD anti-NODasp) CD4+ T cell clones (15). CTL10 is an H-Y-specific, H2-Db-restricted CD8+ T cell clone (16). All T cell clones were maintained in RPMI 1640 medium supplemented with 10% FCS (Globepharm, Esher, U.K.), 2 mM L-glutamine, 100 U/ml penicillin, 100 µg/ml streptomycin, and 5 x 10-5 M 2-ME, in the presence of rhIL-2 (10 U/ml for CD4+ and 20 U/ml for the CD8+ cells) (Boehringer Mannheim, Mannheim, Germany).
Antibodies
The following mAbs were purified from hybridoma culture
supernatants by protein G affinity chromatography (Pharmacia, Uppsala,
Sweden): anti-CD3 (145-2C11, CRL-1975; American Type Culture
Collection (ATCC), Manassas, VA), anti-CD28 (37.51), and
neutralizing anti-IL-4 (11B11, HB188, ATCC) mAbs. A total of 0.6
µg/ml 11B11 mAb was able to neutralize 
1000 U/ml of recombinant
mouse IL-4 in a CTLL-2 bioassay (data not shown). Neutralizing mAbs
specific for murine TGF-ß1, -ß2, -ß3 (code 80-1835-03), for IL-10
(clone JES052A5), and blocking mAb against Fas ligand
(FasL)4 (clone MFL3)
were purchased from Genzyme (Cambridge, MA), R&D Systems (Minneapolis,
MN), and PharMingen (San Diego, CA), respectively. As demonstrated by
other groups, we also observed that these commercial Abs are very
effective in neutralization of cytokine bioactivity or blockage of
killing by murine FasL-transfected cells. The anti-CD4 mAbs (GK1.5
and YTS191) and the anti-CD40 mAb (3/23) (kindly provided by Dr. G.
Klaus) were obtained as culture supernatants. The following
fluorochrome-conjugated reagents were purchased from PharMingen:
PE-conjugated anti-CD11c (HL3); FITC-conjugated anti-rat-MHC
class II (OX-6, which cross-reacts with H2-Ag7);
FITC-conjugated anti-H2-Db (KH95);
FITC-conjugated anti-CD4 (RM4-4); FITC-conjugated anti-CD80
(16-10A1); FITC-conjugated anti-CD86 (GL1); FITC-conjugated
anti-Fas mAb (Jo2); and PE-conjugated anti-CD40L (MR1).
FITC-conjugated goat anti-mouse IgG and FITC-conjugated rabbit
anti-rat IgG were supplied by Sigma (St. Louis, MO) and Dako
(Carpinteria, CA), respectively. FICT-conjugated Annexin V was supplied
by PharMingen.
Induction of T cell anergy in vitro, rechallenge cultures, and mixture experiments
Purified DO.11.10 CD4+ T cells or T cell clones were rendered anergic by immobilized anti-CD3 mAb as previously described (17). Briefly, 2E4 and 1F8 cells isolated from their last restimulation cultures at day 10–14, or purified CD4+ T cells (5 x 105/well), were cultured in 24-well plates precoated with 3–10 µg/ml of purified anti-CD3 mAb. T cells cultured with medium alone served as controls. Two days later, the T cells were isolated, washed, and recultured in fresh medium for at least 2 days. After the rest period, anti-CD3-treated and untreated T cells were tested for proliferative responses to Ag restimulation. Responsive T cells (1 x 104/well) alone, or mixed with irradiated (3000 rad) anergized T cells at a ratio of 1:1 or 1:3, were stimulated with irradiated NODasp DC in 96-well plates for 3 days. The proliferative responses were assessed by [3H]thymidine incorporation during the last 18 h of 96-h assays.
Generation of dendritic cells (DC) from bone marrow cultures
The protocol of Inaba et al. (18) was used to generate DC from bone marrow culture. Briefly, bone marrow cells (5 x 105/ml) were cultured with 10% FCS RPMI 1640 containing 5% supernatant (v/v) from a GM-CSF-secreting transfected cell line. On day 3 of culture, nonadherent cells were removed by gentle pipetting, and the adherent fraction was cultured with a fresh GM-CSF-containing culture medium for a further 4 days. Alternatively, to generate fully mature DC, the bone marrow-derived cells were cultured in the presence of 2 µg/ml of LPS (Sigma) for the last 2 days of culture.
T cell-activating capacity of DC after coculture with anergic T cells
DC (2 x 106) obtained 7 days after
bone marrow culture as the nonadherent fraction, were cultured either
alone or with responsive or anergic T cells (4 x
106) at a 2:1 ratio in 2-ml cultures in 24-well
plates for 48 h. Both responsive and anergic T cells were
irradiated (3000 rad). In some experiments the coculture was performed
in the presence of neutralizing Abs against IL-4, IL-10 and TGF-ß.
For separation of T cells from DC, the DC/T cell cultures were treated
with a cell dissociation solution (Sigma) for 15 min, washed twice, and
then incubated with anti-CD4 mAbs (GK1.5 and YTS191) for 30–45 min
at 4°C while rolling. After two washes the cells were incubated with
sheep anti-rat IgG Dynalbeads (Dynal, Oslo, Norway) for 30–45 min
followed by magnetic separation. The efficiency of T cell depletion was
confirmed by flow cytometric analysis; <5% of cells were CD4 or CD3
positive. No differences in recovery or viability of isolated DC were
observed among cells precultured with medium, responsive or anergic T
cells (see Fig. 5
G). Isolated DC were assayed for their
Ag-presenting capacity by a standard T cell proliferation assay. A
titrated number of irradiated (3000 rad) DC (from 5 x
104 to 3 x 103/well)
was cultured with responder T cells (4 x
104/well) in 96-well plates for 3 days.
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In Transwell assays the cells were separated by a membrane (6.5 mm diameter, 0.4 µm pore size) in 24-well plates (Costar, Cambridge, MA). The lower compartment of the wells contained DC (2 x 106). The upper compartments contained medium alone, anergic, or responsive T cells (2 x 106) with added DC (1 x 106) in 2-ml culture medium. After 48 h, DC were harvested from the lower compartments and tested for their Ag-presenting capacity in T cell proliferation assays.
Flow cytometry
For the characterization of isolated DC populations, cells were stained in PBS, 1% BSA, and 0.1% NaN3 with the mAbs described above. Double stained populations were acquired and the CD11c-gated populations analyzed on a FACSCalibur (Becton Dickinson, Mountain View, CA).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Three mouse T cell clones were used for these experiments; two
independently derived alloreactive clones (1F8 and 2E4) were specific
for the amino acid-substituted NOD H2-A molecule,
NODasp, and CTL10 was specific for a peptide of
the male Ag, H-Y, restricted by H2-Db. The clones
were rendered anergic by culture for 48 h in wells coated with
anti-CD3 mAb in the complete absence of APC. The T cells were
allowed to rest for a further 48 h before restimulation to allow
TCR re-expression. The proliferative unresponsiveness of the two
CD4+ T cell clones after the induction of anergy
is shown in Fig. 1, a and
b. Production of several
cytokines was similarly depressed after culture with anti-CD3
(10). We have reported previously in both human and mouse
systems that anergic T cells inhibit proliferation by other T cells
that interact with the same APC. Fig. 1, c and d,
show the titratable inhibition caused by anergic T cells from these two
T cell clones when responsive T cells were stimulated with
NODasp DC.
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To determine whether the inhibition caused by the anergic T cells
required the presence of APC, T cells were stimulated in the absence of
APC, using coimmobilized anti-CD3 and anti-CD28 Abs. As
presented in Fig. 2a,
irradiated anergic 2E4 T cells caused no inhibition of proliferation by
responsive 2E4 T cells under these conditions. Addition of irradiate,
nonanergized 2E4 T cells led to significant enhancement of
proliferation, presumably due to the secretion of IL-2 by the
irradiated cells that cannot themselves divide and thereby consume
growth factors.
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b. Culture with anergic 2E4 T cells severely compromised
the ability of the DC to restimulate responsive members of the same
clone. In contrast, preculture with responsive members of the same
clone enhanced the immunogenicity of the DC, possibly reflecting the
ability of CD4+ T cells to "license"
DC.
One explanation for these results was that exposure to anergic T cells
led to selective internalization of the "cognate" MHC
molecule:peptide complexes from the DC surface, so that the inability
of the DC to restimulate the clone was due to the lack of cognate
ligand. To test this possibility, the ability of the DC to stimulate
the CD8+ T cell clone, CTL10, after culture with
anergic 2E4 was tested. As displayed in Fig. 2c, the ability
of the DC to induce proliferation by CTL10 was also markedly reduced
after culture with anergic 2E4, indicating that the Ag-presenting
ability of the DC was comprehensively reduced.
To assess the physiological relevance of these findings, we used
freshly purified CD4+ T cells from DO.11.10
TCR-transgenic mice instead of mouse T cell clones. Fig. 2d
shows that anergic CD4+ T cells were also able to
inhibit the Ag-presenting capacity of DC.
To determine whether fully mature DC were susceptible to the inhibitory
effects of anergic T cells, we used bone marrow-derived DC generated in
the presence of GM-CSF and LPS. As shown in Fig. 2e,
preculture with anergic 2E4 T cells caused no inhibition of the
Ag-presenting capacity of LPS-treated DC. Furthermore, preincubation
with responsive 2E4 T cells did not further enhance the immunogenicity
of the DC. These data support previous findings showing that fully
mature DC are refractory to both inhibitory and activating stimuli
(19).
The inhibition of DC function by anergic T cells requires cell:cell contact
One obvious candidate mechanism for these effects was the
secretion of a cytokine, such as IL-10, by the anergic cells which
inhibited DC differentiation and/or function. This was explored in two
ways; first, a series of Transwell experiments was performed. The bone
marrow-derived DC were cultured in the lower chamber, and anergic
cells, with DC, were placed in the upper chamber. The DC in the lower
chamber were tested as APC to stimulate 2E4 T cells after 48 h.
The results presented in Fig. 3a show that no inhibition was
observed when the upper chambers contained anergic T cells and DC,
suggesting that direct contact between the anergic T cells and the DC
is required. Second, neutralizing Abs against IL-4, IL-10, and TGF-ß
were added to cultures containing DC and anergic T cells. As can be
seen in Fig. 3b, the addition of a cocktail of the three Abs
completely failed to protect the DC from the inhibition caused by the
anergic T cells.
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c,
the addition of the Ab did not prevent the inhibition of DC by anergic
T cells. Culture with anergic T cells leads to reduced expression of MHC class II, CD80, and CD86 molecules by DC
Following coculture with anergic or responsive T cells, the
phenotype of the DC was examined by double staining the cells with
anti-CD11c and a variety of Abs specific for key cell surface
molecules. The results are displayed in Fig. 4. After culture in medium alone, the DC
were heterogeneous, containing cells of different stages of maturity.
Indeed, the pattern of CD86 expression suggested that there were two
somewhat distinct populations. Following culture with the responsive T
cells, expression of MHC class II, CD86, and CD40 was up-regulated. For
CD86 this was reflected in an increase in the
CD86high population from 20 to 30%; for MHC
class II and CD40 there was an increase in the mean fluorescence
intensity of the whole population. The levels of expression of MHC
class I and CD80 were slightly decreased and the expression of Fas was
unchanged. In contrast, after 48 h culture with the anergic T
cells expression of MHC class I, CD80, and CD86 was reduced to 40, 45,
and 30% of the control levels, respectively. Expression of CD40 was
increased, although to a lesser extent than following culture with the
responsive T cells (437 vs 500 of mean of fluorescence).
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To determine whether coculture of DC with T cells, either
responsive or anergic, led to apoptosis, DC were stained with
PE-conjugated anti-CD11c and FITC-conjugated-Annexin V. As shown in
Fig. 5, A–C, the staining
profiles in DC preincubated with medium, responsive, or anergic T cells
were identical. Little if any cell death was detectable, in contrast
with cells incubated with anti-Fas mAb (Fig.
5D). Confirmation that the effects of anergic T
cells on DC were not accompanied by cell death was provided by
measuring cell recovery after coculture with T cells. As can be seen in
Fig. 5G, no significant differences in the numbers of
recovered cells were seen under any of the conditions used in these
experiments.
A molecule that has recently been shown to influence DC maturation is
CD40. Ligation of CD40 by CD40L-expressing CD4+ T
cells appears to provide an important differentiation signal for DC
(20, 21, 22). With this in mind, the levels of CD40L expressed
by responsive and anergic T cells were compared. As shown in Fig. 5, E and F, anergic and responsive 2E4 cells
expressed comparable levels of CD40L.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Several groups have reported that anergic T cells, or T cells with a phenotype closely resembling that of an anergic T cell, can act as regulatory cells. We first described this using human cells in an in vitro system (7, 8). More recently we demonstrated that anergic mouse T cells can prolong skin allograft survival (10). Similar phenomena have been described using rat T cells in vitro; a requirement for the presence of APC for this inhibition to be observed was also noted in this study (23). The third set of related findings have emerged from the study of day three thymectomized mice that develop a variety of autoimmune pathologies spontaneously (12), and lack a small population of CD4+, CD25+ peripheral T cells. The significance of these cells became apparent when they were adoptively transferred from a normal, into a day three thymectomized mouse, in that they protected the recipients from the onset of autoimmune disease. When characterized functionally in vitro, these CD4+, CD25+ cells had the characteristics of anergic T cells, in that they could not undergo autocrine proliferation, made little if any cytokines, but could proliferate in response to exogenous IL-2. Furthermore, they were potent inhibitors of proliferation and IL-2 secretion by normal T cells.
DC are professional bone marrow-derived APC that play a dominant role
in the initiation and regulation of immune responses. They exhibit
phenotypic and functional diversity that is related to their stage of
maturation (24) and/or to their myeloid or lymphoid origin
(25). Culture of bone marrow cells with GM-CSF alone does
not yield fully mature DC, but induces an intermediate state of
maturation with respect to phenotype and Ag-presenting capacity
(24, 26). It has also been reported that bone
marrow-derived immature DC can induce hyporesponsiveness in allogeneic
T cells (27) and significantly prolong cardiac allograft
survival when injected into recipient mice (28). Previous
studies have reported that the contact between activated T cells and
DC, involving several members of the TNF family, induces maturation and
activation of DC with subsequent enhancement of expression of MHC and
costimulatory molecules (29). Culture of bone
marrow-derived DC with anergic T cells had the opposite effect in that
the immunogenicity of the DC was profoundly diminished, and expression
of MHC class II, CD80, and CD86 molecules was reduced. However, it is
not clear whether the impaired Ag-presenting capacity of the DC can be
explained only by the decreased expression of MHC class II and
costimulatory molecules, or whether additional mechanisms are involved.
The responsive and anergic T cells expressed comparable levels of CD40L
(Fig. 5, E and F), suggesting that lack of CD40
ligation did not contribute to the observed effects of anergic T
cells.
The functional and phenotypic analysis of the DC after culture with
anergic T cells suggest that a negative signal was delivered to the DC
that both caused maturation arrest, and down-regulated the most mature
cells in the cultures. An alternative possibility was that the most
mature cells were selectively killed as a result of culture with
anergic T cells. This did not appear to be the case, in that the same
numbers of cells were recovered from the different culture conditions
(Fig. 5G), and Annexin V staining did not indicate apoptosis
of CD11c+ cells (Fig. 5, A–D).
Several cytokines have been shown to affect the differentiation and
function of DC. TGF-ß and IL-10 can suppress DC functions and
interfere with DC maturation (24). However the inhibition
of DC function by anergic T cells required cell:cell contact and
addition of neutralizing Abs specific for IL-4, IL-10, and TGF-ß
failed to protect the DC from the inhibitory effects of anergic T
cells. These results are in accordance with our and other previous
findings showing that the regulatory effects of anergic T cells are not
mediated by soluble factors (7, 8, 23). Furthermore, the
inhibition of DC functions by anergic T cells seems not to be due to
Fas-FasL interaction as showed in Fig. 3c; however, the
molecular basis of this mechanism remains undefined.
The critical question is how this mechanism might contribute to physiological immunoregulation in vivo. The most extensively studied means of inducing T cell anergy in vitro has been costimulation-deficient Ag presentation. We, and others, have demonstrated that Ag presentation by primary cultures of allogeneic epithelial cells from the thyroid, or the kidney, induce allospecific hyporesponsiveness in resting (30) and recently activated (31) peripheral blood CD4+ T cells. This is likely to be a prominent event, in vivo, once tissue inflammation is well established, and parenchymal cell MHC class II expression has been induced. Such costimulation-deficient Ag presentation is likely to induce a cohort of anergic T cells with the potential to inhibit the Ag-presenting capacity of newly recruited DC, and thereby help to damp down the inflammatory response. In the context of transplantation, the suppressive effects of anergic T cells may be most relevant to inhibiting the indirect pathway of allorecognition by down-regulating recipient DC as they traffic through the graft before they present donor-derived peptides in the draining lymph node.
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Footnotes |
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2 S.V. and J.-G.C. are co-first authors.
3 Address correspondence and reprint requests to Dr. Robert Lechler, Department of Immunology, Imperial College School of Medicine, Hammersmith Hospital, Du Cane Road, London, U.K. W12 ONN.
4 Abbreviations used in this paper: FasL, Fas ligand; DC, dendritic cells; CD40L. CD40 ligand.
Received for publication November 29, 1999. Accepted for publication April 24, 2000.
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and to bacterial IL-12 inducers: decreased ability of mature dendritic cells to produce IL-12 during the interaction with Th cells. J. Immunol. 162:3231.This article has been cited by other articles:
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T. Bonnefoix, P. Bonnefoix, J.-Q. Mi, J.-J. Lawrence, J.-J. Sotto, and D. Leroux Detection of Suppressor T Lymphocytes and Estimation of Their Frequency in Limiting Dilution Assays by Generalized Linear Regression Modeling J. Immunol., March 15, 2003; 170(6): 2884 - 2894. [Abstract] [Full Text] [PDF]
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 K. J. Maloy, L. Salaun, R. Cahill, G. Dougan, N. J. Saunders, and F. Powrie CD4+CD25+ TR Cells Suppress Innate Immune Pathology Through Cytokine-dependent Mechanisms J. Exp. Med., January 6, 2003; 197(1): 111 - 119. [Abstract] [Full Text] [PDF]
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L. Frasca, C. Scotta, G. Lombardi, and E. Piccolella Human Anergic CD4+ T Cells Can Act as Suppressor Cells by Affecting Autologous Dendritic Cell Conditioning and Survival J. Immunol., February 1, 2002; 168(3): 1060 - 1068. [Abstract] [Full Text] [PDF]
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D. Zelenika, E. Adams, S. Humm, L. Graca, S. Thompson, S. P. Cobbold, and H. Waldmann Regulatory T Cells Overexpress a Subset of Th2 Gene Transcripts J. Immunol., February 1, 2002; 168(3): 1069 - 1079. [Abstract] [Full Text] [PDF]
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 M. F. Lipscomb and B. J. Masten Dendritic Cells: Immune Regulators in Health and Disease Physiol Rev, January 1, 2002; 82(1): 97 - 130. [Abstract] [Full Text] [PDF]
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W. F. Ng, P. J. Duggan, F. Ponchel, G. Matarese, G. Lombardi, A. D. Edwards, J. D. Isaacs, and R. I. Lechler Human CD4+CD25+ cells: a naturally occurring population of regulatory T cells Blood, November 1, 2001; 98(9): 2736 - 2744. [Abstract] [Full Text] [PDF]
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 R. W. Tindle, K. Herd, T. Doan, G. Bryson, G. R. Leggatt, P. Lambert, I. H. Frazer, and M. Street Nonspecific Down-Regulation of CD8+ T-Cell Responses in Mice Expressing Human Papillomavirus Type 16 E7 Oncoprotein from the Keratin-14 Promoter J. Virol., July 1, 2001; 75(13): 5985 - 5997. [Abstract] [Full Text] [PDF]
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S. Yamagiwa, J. D. Gray, S. Hashimoto, and D. A. Horwitz A Role for TGF-{{beta}} in the Generation and Expansion of CD4+CD25+ Regulatory T Cells from Human Peripheral Blood J. Immunol., June 15, 2001; 166(12): 7282 - 7289. [Abstract] [Full Text] [PDF]
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E. M. Shevach Certified Professionals: Cd4+Cd25+ Suppressor T Cells J. Exp. Med., June 4, 2001; 193(11): f41 - f46. [Full Text] [PDF]
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S. Auffermann-Gretzinger, E. B. Keeffe, and S. Levy Impaired dendritic cell maturation in patients with chronic, but not resolved, hepatitis C virus infection Blood, May 15, 2001; 97(10): 3171 - 3176. [Abstract] [Full Text] [PDF]
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K. Leon, R. Perez, A. Lage, and J. Carneiro Three-Cell Interactions in T Cell-Mediated Suppression? A Mathematical Analysis of Its Quantitative Implications J. Immunol., May 1, 2001; 166(9): 5356 - 5365. [Abstract] [Full Text] [PDF]
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A. Snijders, D. G. Elferink, A. Geluk, A. L. van der Zanden, K. Vos, G. M. T. Schreuder, F. C. Breedveld, R. R. P. de Vries, and E. H. Zanelli An HLA-DRB1-Derived Peptide Associated with Protection Against Rheumatoid Arthritis Is Naturally Processed by Human APCs J. Immunol., April 15, 2001; 166(8): 4987 - 4993. [Abstract] [Full Text] [PDF]
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P. Alard, C. Thompson, S. S. Agersborg, J. Thatte, Y. Setiady, E. Samy, and K. S. K. Tung Endogenous Oocyte Antigens Are Required for Rapid Induction and Progression of Autoimmune Ovarian Disease Following Day-3 Thymectomy J. Immunol., April 1, 2001; 166(7): 4363 - 4369. [Abstract] [Full Text] [PDF]
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 A. Lanzavecchia and F. Sallusto Dynamics of T Lymphocyte Responses: Intermediates, Effectors, and Memory Cells Science, October 6, 2000; 290(5489): 92 - 97. [Abstract] [Full Text]
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