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*
Faculty of Medicine, Memorial University of Newfoundland, St. John’s, Newfoundland, Canada;
Department of Immunology, Hellenic Pasteur Institute, Athens, Greece;
Department of Immunobiology, Guy’s, King’s College, and St. Thomas’s Hospitals’ Medical and Dental Schools, London, United Kingdom; and
§
Department of Immunology and Microbiology, Wayne State University School of Medicine, Detroit, MI 48202
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Abstract |
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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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In this study, we have used thyroglobulin (Tg) as a model Ag to examine whether processing of Tg-Ab complexes would generate pathogenic but nondominant T cell epitopes. Tg is a 660-kDa homodimer, the largest autoantigen known, that causes experimental autoimmune thyroiditis (EAT), a T cell-mediated disease considered as a model for Hashimoto’s thyroiditis (HT) in humans (11). Two observations render Tg an ideal choice for this study. First, none of the known pathogenic T cell epitopes in Tg has been classified as dominant in EAT studies (12). Second, a large percentage of patients with HT, and almost invariably all animals developing EAT, have circulating Tg-specific Abs. It remains unclear whether such Abs play a role in promoting the generation of cryptic pathogenic epitopes.
We have developed T cell hybridoma clones against two pathogenic MHC class II-binding peptides at the C-terminal end of Tg: the subdominant peptide (2549–2560), which is derived from processing of Tg in vivo but not in vitro (13, 14), and the cryptic peptide (2495–2511), which is not generated following processing of intact Tg either in vivo or in vitro (15). The aim of the study was to examine whether mAbs bound to Tg would interfere with Tg uptake or processing by APC and promote the generation of these two peptides.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The 17-mer Tg peptide (2495–2511) Ac-GLINRAKAVKQFEESQG-NH2) (15) and the 12-mer Tg peptide (2549–2560), NH2-STDDT4ASFSRAL-NH2 (containing thyroxine (T4) at amino acid position 2553 (T4(2553)) (16) were synthesized and purified as previously described. Both peptide sequences are part of the mouse Tg sequence (17). Tg was purified from frozen thyroid glands of outbred ICR mice (Bioproducts for Science, Indianapolis, IN) by passing thyroid homogenates through a Sepharose CL-4B column (15). The fractions of peak II were pooled, concentrated to 3–5 mg/ml PBS, filter sterilized, and stored at -20°C until use. In all assays, Tg concentrations are expressed as the molarity of the monomeric form (330 kDa).
Culture medium and cell lines
All assays were performed in DMEM (Life Technologies,
Burlington, Ontario, Canada) supplemented with 10% FBS (Bioproducts
for Science), 10 mM HEPES buffer, 2 mM L-glutamine, 100
U/ml penicillin, and 100 µg/ml streptomycin (all from Life
Technologies) and 5 x 10-5 M 2-ME (Sigma, St. Louis,
MO). The TA3 cell line, produced by fusion of B cells from
CAF1 mice with the M12.4.1 BALB/c B lymphoma (18), was
kindly provided by L. Glimcher (Harvard Medical School, Cambridge, MA).
TA3 cells are known to express Ak/d, Ek/d,
KdDd, IgG, 
-chain, and Fc
R molecules,
while they are negative for IgM, IgD, Thy-1.2, and Kk (18, 19). The IL-2-dependent CTLL-2 line (20) was purchased from the
American Type Culture Collection (ATCC; Manassas, VA). The T cell
hybridoma 3.47 clone was generated following a modified method of
Perkins et al. (21). Briefly, lymph node cells (LNC) from CBA/J mice,
immunized with mouse Tg, were further stimulated in vitro with the same
Ag and fused with BW5147 
-ß- cells (22)
(a kind gift of P. Marrack, Howard Hughes Medical Institute, Denver,
CO) using polyethylene glycol 1500 (Boehringer Mannheim, Indianapolis,
IN). Screening and cloning were performed as previously described (23).
The 3.47 clone is CD4+ by FACS and is Ak
restricted as assessed by mAb inhibition of activation (data not
shown). The 8F9 T cell hybrid clone (CD4+ and
Ek restricted) was similarly produced from LNC of B10.BR
mice primed and boosted with the pathogenic Tg peptide (2495–2511).
Purification and characterization of mAbs
The previously characterized 5D2, 3B3, 2A4, and 3C4 mAbs (24) were produced from hybridomas formed between spleen cells from BALB/c mice immunized with human Tg and mouse myeloma NSI/I.Ag 4.1 cells. They were purified from culture supernatants by affinity chromatography on protein G-Sepharose 4 Fast Flow columns (Pharmacia, Baie d’Urfé, Quebec, Canada) and dialyzed in PBS. The 55H8 mAb was also derived from human Tg-primed BALB/c splenic cells fused with the mouse myeloma NSO and were similarly purified from ascites fluid. The purified material was concentrated to 1–2 mg/ml PBS, filter sterilized, and stored at -20°C until use. All mAbs are of the IgG1 subclass except for 5D2, which is IgG2b. Isotyping was performed using the ISO-2 kit (Sigma) and peroxidase-conjugated rabbit anti-goat IgG (Sigma A5420) (data not shown). Fragmentation of 3C4 to F(ab')2 was done using preactivated papain as described (25). The purity of the F(ab')2 preparation was confirmed by SDS-PAGE, and its binding to Tg was verified by ELISA. The rat anti-mouse FcR mAb 2.4G2 (IgG2b) was purified by affinity chromatography on protein G-Sepharose from supernatants of HB 197 cells (ATCC).
ELISA and RIA
The mAbs were tested for reactivity against mouse Tg or Tg peptides by ELISA (15) using Fc- or Fab-specific alkaline phosphatase-conjugated goat anti-mouse IgG (Sigma) as the second Ab. Absorbance at 405 nm was measured using a microplate reader (Vmax, Molecular Devices, Menlo Park, CA). To monitor IC uptake by APC, Tg was 125I labeled using Iodogen (Pierce, Rockford, IL) and 125I-labeled sodium (DuPont Canada, Mississauga, ON) according to the manufacturer’s protocol. All free 125I-labeled sodium was removed by extensive dialysis before IC formation. Potential cross-reactivity for pairs of mAbs was assessed by RIA based on competitive inhibition. Briefly, wells of microtiter polyvinyl chloride plates (Dynatech, Chantilly, VA) were coated by a Tg-specific mAb (30 µg/ml), and 125I-labeled Tg (240,000 cpm/µg) was allowed to bind to the wells in the presence of increasing amounts of a second Tg-specific mAb. After washing and drying, the wells were cut and counted in a gamma counter (Wallac, Gaithersburg, MD).
T cell activation assay
ICs of Tg and mAbs were formed in DMEM in triplicate wells of 96-well culture plates. One hour later, 105 TA3 and 105 T cells were added in a total volume of 200 µl/well. Following a 24-h incubation, 100 µl of supernatant was removed and stored at -20°C for assessment of IL-2 release, as measured by the proliferation of the CTLL-2 line using [3H]thymidine (DuPont Canada). Fixation of TA3 was performed by suspending 4 x 106 cells/ml in 0.05% glutaraldehyde. After 30 s, the reaction was stopped by the addition of an equal volume of 0.2 M glycine.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Initial testing by ELISA confirmed that the five mAbs, 5D2, 3C4,
3B3, 2A4, and 55H8, which were raised against human Tg, cross-reacted
significantly with mouse Tg (Fig. 1
A). Some differences in
binding were, however, observed, with 5D2 and 55H8 mAbs exhibiting a
10- to 15-fold better binding to mouse Tg than the others. To directly
assess mAb-mediated uptake of Tg by APC, we pulsed TA3 cells for 6
h with 200 nM of 125I-labeled Tg either in a free form or
complexed to various mAbs, and the cell-bound radioactivity was
subsequently measured. It was observed that all mAbs significantly
enhanced Tg uptake by TA3 and that this effect was abolished in the
presence of anti-FcR mAb (Fig. 1B). In preliminary work,
all mAbs were shown to exhibit similar binding to native or highly
iodinated Tg in ELISA (data not shown).
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To follow the processing of Tg-mAb complexes, we monitored the
generation of two neighboring pathogenic peptides, T4(2553) and
(2495–2511), using TA3 as APC. The first peptide was serendipitously
found to activate 3.47, an Ak-restricted T cell hybridoma
clone that was, nevertheless, unreactive to equimolar concentrations of
intact Tg (Fig. 2A).
Processing of Tg bound to 5D2 and 3C4 boosted presentation of the
T4(2553) epitope that was now detectable at 5–10 nM (Fig. 2B), whereas the 2A4-Tg complex was 10- to 20-fold less
efficient. On the other hand, binding of 3B3 and 55H8 mAbs to Tg had no
augmenting effect on the generation of T4(2553), despite the fact that
they enhanced Tg uptake by TA3. The boosting effect did not correlate
either with the mAb IgG subclass (e.g., 3C4, 3B3, and 55H8 are all
IgG1) or with the relative mAb binding to Tg (e.g., 5D2 and 3C4 augment
equally well the generation of T4(2553)).
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C).
However, unlike 3.47, 8F9 did not respond to TA3 cocultured with any of
the above Tg-mAb complexes (Fig. 2D). Since 5D2 and 3C4
lowered the threshold for presentation of the T4(2553) peptide without
boosting the presentation of the second determinant localized 38 aa
upstream, the boosting effect of these mAbs could not be attributed
solely to enhanced Tg uptake by the complexes. These results suggested
that 5D2 and 3C4 exerted a selective augmenting effect by interfering
with the loading of the T4(2553) epitope on Ak molecules
during Tg processing. 5D2 and 3C4 mAbs interfere with Tg processing
To exclude the possibility that the 5D2 and 3C4 mAbs exerted
signaling effects on TA3 that would generally augment Ag presentation,
we titrated Tg or T4(2553) in the presence or absence of a fixed amount
of mAb followed by the addition of TA3 and 3.47 T cells. 3.47 was again
activated only after processing of Tg-mAb complexes, not intact Tg
(Fig. 3A). In contrast, 5D2
and 3C4 showed no boosting effect on T4(2553) presentation when free
peptide was used as Ag (Fig. 3B), which argues against
non-Ag-specific signaling effects of these mAbs on TA3. Addition of
chloroquine in the culture abrogated the enhancing effect of 5D2 or 3C4
on the presentation of the T4(2553) peptide following Tg processing but
did not influence the activation of 3.47 cells by TA3 pulsed with free
peptide (Fig. 3C). Finally, glutaraldehyde-fixed TA3 cells
pulsed with Tg-5D2 or Tg-3C4 complexes did not activate the 3.47 clone
but retained the capacity to present free T4(2553) peptide to the same
T cells (Fig. 3D). These data indicated that 5D2 and 3C4
exert their effects during Tg processing either by facilitating the
generation of the T4(2553) peptide or by augmenting the loading of this
epitope on Ak molecules.
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Following digestion with preactivated papain, we obtained
F(ab')2 fragments from the 3C4 mAb. In ELISA, these
F(ab')2 fragments retained Tg-binding activity similar to
that of intact 3C4 (data not shown). It was subsequently observed,
however, that TA3 pulsed with Tg bound to 3C4 F(ab')2 did
not activate the 3.47 clone (Fig. 4A). Also, addition of
increasing amounts of FcR-specific mAb in TA3 cultures completely
blocked the activation of 3.47 mediated by 5D2-Tg or 3C4-Tg complexes,
whereas the same treatment had no effect on the stimulation of 3.47 by
free T4(2553) peptide (Fig. 4B). These results demonstrated
that the FcR-mediated uptake of Tg-Ab complexes by TA3 is a necessary
step for the formation of the T4(2553) epitope.
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We subsequently screened by ELISA all mAbs for potential
reactivity against the two Tg peptides. The 55H8 mAb was reactive with
the T4(2553) epitope (Fig. 5A), whereas the 5D2 mAb bound
specifically to (2495–2511) (Fig. 5B). None of the other
mAbs reacted with either of these two peptides. This observation
explained the lack of augmenting function by 55H8 and further suggested
that 55H8 might prevent loading of T4(2553) on Ak molecules
during Tg processing, possibly due to peptide sequestration, as
predicted by the T cell:B cell reciprocity hypothesis (5, 6). To test
this, equimolar amounts of 55H8, Tg, and a boosting mAb (3C4 or 5D2)
were mixed in wells of microtiter plates in the presence of TA3 and
3.47 T cells. The 3B3 mAb, which cannot augment presentation of
T4(2553) (Fig. 2B) and does not bind to it (Fig. 5A), was used as control. It was found that 55H8 abolished
the augmenting effects of 3C4 or 5D2 mAbs on the generation of this
determinant, whereas the control 3B3 mAb was ineffective (Fig. 6A). This dominant suppressive
effect was also prevalent when all three potentiating mAbs, 5D2, 3C4,
and 2A4, were cocultured with Tg and 55H8 (Fig. 6B). 55H8
did not interfere with the binding of the enhancing mAbs due to steric
hindrance. As shown in Fig. 5C, none of the available mAbs
could inhibit binding of Tg to 55H8 in a competitive inhibition
RIA. Similarly, the lack of suppressive effects by 3B3 could
not be explained by abrogation of binding due to interference;
none of the mAbs inhibited binding of radiolabeled Tg to 3B3 (Fig. 5D).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The failure of 3C4 to boost generation of the cryptic (2495–2511) peptide provides a clear example of a qualitative effect on Tg processing. This soluble mAb, piggybacked on Tg, enhances Tg capture by TA3, but this does not lower the activation threshold for (2495–2511) to allow its detection by the 8F9 clone. How can the 3C4 mAb that binds to a monomeric Tg subunit of 2748 aa residues have such contrasting effects on the generation of two epitopes that are only 38 aa apart? 3C4 does not bind to (2495–2511), and thus a plausible interpretation would be that endosomal proteases trim the 3C4-bound fragment of Tg and remove the (2495–2511) peptide because it is localized beyond the boundary of 3C4 protection. Thus, it is conceivable that mAbs with different specificities from the ones used here will be found to promote presentation of (2495–2511).
The TA3 line has been produced after fusion of B cells with a B cell lymphoma, and its inefficiency in the processing of intact Tg is paradoxical, since the rate of fluid-phase pinocytosis in B cell tumors is 10- to 60-fold higher than that of B cells (27). In earlier studies, Hutchings et al. (28) demonstrated that B cells from Tg-primed mice presented low amounts of Tg (1 µg/ml) to a T cell hybridoma clone that was subsequently found to react with (2549–2560) (29). Our data and those findings demonstrate that Tg-reactive IgG either in soluble form or as sIg on B cells can mediate enhanced Tg uptake by receptor-mediated endocytosis and modulate Tg processing to enhance the generation of this pathogenic epitope. Interestingly, the above data (28) also imply that B-cell clones bearing the 55H8 specificity do not occur with high frequency in Tg-primed spleen cells, but this interpretation requires caution, since the 55H8 mAb was elicited after challenge with human Tg, whereas Hutchings et al. (28) used a pool of mouse, dog, and rat Tg for immunizations.
Other investigators have similarly reported that Abs bound to foreign
(30, 31, 32) or self (33) Ags can modulate presentation of T cell
determinants. In apparent contrast to our data, Fab fragments did
mediate enhanced presentation of peptide Ag in some studies (31), but
the APC were EBV-transformed, tetanus toxin-specific B cell clones that
constitutively internalized IC via their sIg. When B-cell lymphomas
were used as APC, use of F(ab')2 fragments in IC did not
improve Ag presentation (30), and FcR-specific Abs blocked T cell
activation (30, 33), suggesting FcR-mediated augmentation of Ag uptake
and presentation. Other FcR-expressing APC such as macrophages or
dendritic cells might similarly process Tg-Ab complexes to generate the
peptides studied here, but the outcome of the response is difficult to
predict, given that distinct sets of proteases may be active in
different APC (34). Assays based on adoptive transfer of Ag-specific
LNC have clearly shown that the nondominant pathogenic (2495–2511)
and/or T4(2553) peptides are generated within the mouse (13, 15, 16) or
rat (35) thyroid, possibly via processing of Tg or Tg fragments by
intrathyroidal dendritic cells (36).
Ab-mediated suppression of Tg peptide generation is exemplified by the 55H8 mAb that binds to T4(2553) on Tg and may sequester this epitope from loading onto Ak molecules. This interpretation is in agreement with the T cell:B cell reciprocity hypothesis (5, 6), according to which the sIg on B cells, or soluble Ab bound on Ag, can at times negatively steer Ag processing because the part of the Ag within the Ab-combining site is protected from proteolysis and prevented from subsequent loading onto MHC class II molecules. A corollary of this hypothesis would be that soluble 55H8 piggybacked on Tg would exert a dominant suppressive effect on the generation of this pathogenic epitope. This is fully supported by our data; when mixtures of potentiating mAbs and 55H8 were incubated with Tg, suppression was dominant. Suppression could not be attributed to 55H8 blockade of the T4(2553)-Ak complex, because the same 5D2-Tg-55H8 IC preparations did not affect presentation of free peptide on TA3 (our unpublished data). A reciprocal relationship is also highlighted by the 5D2 mAb and the (2495–2511)-specific 8F9 clone, which recognize overlapping determinants within (2495–2511); this peptide cannot be generated during processing of 5D2-Tg complexes in TA3, because the T and B cell epitopes physically overlap. To our knowledge, our findings provide the first examples that directly support the T cell:B cell reciprocity hypothesis in autoimmune disease.
The present study reveals an immunoregulatory role for Tg-specific IgG Abs that are quite frequent in HT and include all four subclasses (37, 38, 39). The chronicity of the disease favors generation of high affinity IgG1 and IgG4 Abs (40), and it has been suggested that rising titers of high affinity IgG1 anti-Tg may be indicative of impending hypothyroidism (40). As extrapolated from our data, such high affinity autoantibodies may have a neutral, suppressive, or augmenting effect on the generation of pathogenic Tg T cell determinants, depending on the epitopes they recognize and the genetic background of the individual. In some cases, their net effect could be exacerbation of disease and the spreading of the autoimmune response to nondominant T cell epitopes (41). At present, a more direct testing of this hypothesis with Tg-reactive human CD4+ T cell clones is not feasible, because the epitopes they recognize remain unknown. In addition, we do not know whether Tg-specific human autoantibodies in HT recognize linear or conformational determinants (37) and where these determinants are precisely localized. Several studies suggest, however, that autoreactive IgG in the serum of HT patients binds to a limited number of Tg epitopes (24, 39, 42, 43, 44), including an immunodominant central region (aa 1149–1250) (45). Autoreactive, Tg-specific Abs may be induced by foreign Ags via molecular mimicry and gradually promote the generation of nondominant pathogenic T cell epitopes, as suggested in other systems (8). Our data are not incompatible with this concept and support the notion that Tg-reactive Abs may play a much more complex role in the regulation of thyroid disease than previously anticipated.
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Acknowledgments |
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-ß- cells and Dr. L.
Glimcher for the TA3 cell line. |
Footnotes |
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2 Address correspondence and reprint requests to Dr. George Carayanniotis, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, NF Canada, A1B 3V6. E-mail address:
3 Abbreviations used in this paper: IC, immune complex; Tg, thyroglobulin; EAT, experimental autoimmune thyroiditis; HT, Hashimoto’s thyroiditis; T4, thyroxine; T4(2553), peptide (2549–2560) with T4 at amino acid position 2553; LNC, lymph node cell.
Received for publication September 16, 1998. Accepted for publication March 22, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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RII on human B cells can mediate enhanced antigen presentation. Cell. Immunol. 167:188.[Medline]
receptor II dependency of enhanced presentation of major histocompatibility complex class II peptides by a B cell lymphoma. Eur. J. Immunol. 27:1022.[Medline]
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