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Department of Cancer Immunology and AIDS, Dana Farber Cancer Institute, Department of Pathology, Harvard Medical School, Boston, MA 02115
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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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Primary and secondary Ab responses to foreign Ags can be suppressed by CD8 T cells (5, 6, 7). A central and unresolved issue is whether suppressive CD8 cells recognize cellular peptides and MHC molecules and use this interaction to generate or mediate suppressive activity. Data from human models indicate that CD8-suppressive cells may recognize Ag in the context of MHC class II molecules (4, 8), while murine suppressor cells have been characterized most often as "I-J restricted" (9, 10), although the relationship of this entity to MHC products remains unclear.
Here we attempt to determine whether MHC products are involved in CD8-mediated inhibition of the classical anti-SRBC model (11), using mice that carry a targeted disruption of the ß2-microglobulin (ß2m)3 gene (12). These mice lack cell surface expression of the classical MHC class I products known to be important for presentation of peptides to CD8 cells. In addition, ß2m-/- mice do not express nonclassical class I molecules, including Qa-1, which is expressed at higher levels on activated T and B lymphocytes (13, 14) and has been implicated in immunoregulation (15, 16). Our findings suggest a novel pathway leading to CD8 cell-dependent inhibition of Th cells, which depends on stimulation of CD8 cells by Qa-1 on activated B cells.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C57BL/6 (ß2m+/+) and
C57BL/6-ß2m-/- mice, the latter obtained
after nine generations of backcrossing to C57BL/6 (B6) mice, were used
for all experiments except that shown in Figure 3
, which was conducted
using (C57BL/6x129)F2 ß2m+/+ or
(C57BL/6x129)F2 ß2m-/- mice
(see legend to Fig. 3). In addition, B6.A.Tlaa.BoyEG
(B6.Tlaa) mice were purchased from The Jackson Laboratory
(Bar Harbor, ME). Age- and sex-matched experimental groups were
immunized with SRBC in 200 µl PBS i.p.
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SRBC and Low-Tox rabbit complement were purchased from Accurate
Chemical (Westbury, NY), horse RBC (HRBC) from New England Immunology
Associates (Cambridge, MA), and rabbit antiserum to mouse IgG from
Cappel (Durham, NC). HO-13-4, 3.155, 25-9-3S, and J11D.2 hybridomas
producing anti-Thy-1, CD8, MHC class II, and anti-B cell Abs,
respectively, were obtained from American Type Culture Collection
(Rockville, MD). RL172.4 (anti-CD4) was a gift from Dr. R. Dick
(Ben May Institute, Chicago, IL). Anti-CD4, anti-CD8, and
anti-B220 fluorescent mAbs and anti-IFN-
(XMG1.2 mAb) were
purchased from PharMingen (San Diego, CA). Anti-Qa-1a
and Qa-1b antisera were a gift from Dr. L. Flaherty
(Wadsworth Center for Laboratories and Research, Albany, NY). Normal
mouse sera and RBCs were collected from untreated B6 mice.
Anti-rat/mouse IgG M450 Dynabeads were from Dynal (Lake Success, NY).
Other reagents were purchased from Sigma (St. Louis, MO). All cell
preparations and fractionations were performed in DMEM + 2%
FBS + HEPES (1 mM). Cell culture medium was DMEM + 10%
FBS + L-glutamine (2 mM), sodium pyruvate (1 mM),
HEPES (1 mM), nonessential amino acids (1 mM each), gentamicin (50
µg/ml), and 2-ME (50 µM).
Cell purifications
B cells were purified by depletion of T cells from splenocytes using anti-Thy-1 (HO-13-4), anti-CD4 (RL172.4), and anti-CD8 (3.155) hybridoma supernatants (1/20 each), followed by rabbit complement. These cells were >90% B cells and <1% T cells as assessed by flow cytometry after staining with anti-B220-PE and anti-CD4-PE or anti-CD8-FITC mAbs. In some experiments, highly purified B cells were prepared by removing adherent cells from splenocytes on petri dishes (107/ml at 37°C for 1 h) followed by depletion of T cells as above and by subsequent positive selection of B cells using anti-rat/mouse IgG Dynabeads (107 beads/107 cells, incubated for 25 min on a rotator at 4°C). Attached cells were >97% B220+. CD4 and CD8 cells were purified from lymph node cells by complement depletion using anti-CD4 (RL172.4) or anti-CD8 (3.155), anti-class II (25-9-35), and anti-B cell (J11D.2) mAbs (all 1/4 dilution) + rabbit C. CD4 cells were >90% CD4+ and <0.2% CD8+; CD8 cells were >85% CD8+ and <3% CD4+. Splenic adherent cells (SAC) were prepared by depletion of both T and B cells as described above. Cells were then irradiated (2500 rad) and incubated in microtiter plates at 5 x 105/well for 1 h. Nonadherent cells were washed from the wells before addition of B and T cells.
In vivo anti-SRBC IgM and IgG responses
Mice were immunized with SRBC and splenocytes were recovered at various time points. Unfractionated spleen cells were diluted to 107/ml and anti-SRBC plaque-forming cells (pfc) were determined using the Cunningham plaque assay as described (17). For the measurement of IgG pfc, rabbit antiserum to mouse IgG was added to the plaquing mixture at an optimized dilution (1/1000) to allow detection of both IgM and IgG plaques (18). IgM pfc obtained in the absence of antiserum were subtracted from the total to obtain IgG pfc. Results were expressed as pfc per 106 splenocytes.
In some experiments, mice were primed with 107 LPS blasts from B6 or ß2m-/- mice on days 0 and 5, then immunized with 108 SRBC on day 10. LPS blasts were prepared by positive selection of B cells from untreated splenocytes using Dynabeads as described above. B cells were then activated at 2 x 106/ml for 2 days with 10 µg/ml LPS, and washed in PBS before use. Blasts were >99% B220 positive.
In vitro anti-SRBC IgM responses
A modified version of the model described by Hu et al. was used (19). Spleen and lymph node cells from mice immunized 4 days previously with 2 x 107 SRBC were prepared. Cell cultures (200 µl) were set up in flat-bottom microtiter plates using 5 x 105 B cells, 105 CD4 and/or CD8 cells, and 106 SRBC per well. Plates were incubated at 37°C, 5% CO2 for 5 days. Cells were then washed and anti-SRBC pfc were determined using the Cunningham plaque assay (17). Results were expressed as numbers of pfc per well and are means ± SEM from triplicate cultures. In some cases, results are expressed as a percentage of suppression of control cultures containing no CD8 cells.
HSV inoculation and clinical scoring
Mice were anesthetized with pentobarbital before the right eye of each mouse was scratched with a 25-gauge needle (five horizontal and five vertical scratches). Five microliters of herpes simplex virus-1 (HSV-1) (KOS strain) suspension were deposited onto the scarified cornea. A standard scoring system for incidence of herpes stromal keratitis (HSK) based on the degree of cloudiness and opacity on the cornea was used to assess the severity of the disease (20).
ELISA
Virus-specific IgM and IgG levels were determined by ELISA.
Serum samples from B6 or ß2m-/- mice
immunized previously with HSV-1 (KOS strain, 5 x 106
PFU/mouse i.p.) were obtained individually. Microtiter plates were
coated with 100 µl of 1:50 dilution of a 107 PFU/ml of
HSV-1 (grown in VERO cells) in PBS overnight. After blocking and
washing three times, 100 µl of the appropriate dilution of serum
samples was added to triplicate wells for at least 3 h at room
temperature. The plates were washed and alkaline phosphatase-conjugated
goat anti-mouse IgG (-chain specific) or IgM (µ-chain
specific) (Sigma) were added at dilutions that produce optimum specific
binding. The plates were incubated overnight at 4°C. After washing,
200 µl of p-nitrophenyl phosphate liquid substrate (Sigma)
was added to each well. After a 45-min incubation, the reaction was
stopped by addition of 50 µl of 3 N NaOH to each well. Absorbance was
measured at 405 nm. Pooled serum from HSV-1-immunized mice was used as
a positive control.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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ß2-m knockout (ß2m-/-)
mice are deficient in cell surface expression of MHC class I products
and, consequently, contain very few mature CD8 T cells. The in vivo Ab
response of these mice was initially determined after immunization with
a relatively high dose of SRBC, which has been reported to induce CD8
suppression (21). The IgM response of
ß2m-/- mice was four times greater than the
response of syngeneic control (ß2m+/+) mice
(Fig. 1A). We also compared
the in vivo response of ß2m-/- and control
mice to lower doses of SRBC (108/mouse) to further assess
the effect of class I/CD8-associated regulation of a primary Ab
response (Fig. 1B). The ß2m-/-
mice generated a stronger initial IgM response, as assessed by splenic
anti-SRBC pfc at day 5 when compared with control mice and the
long-term Ab response in ß2m-/- mice was
approximately twice as great as ß2m+/+
control mice in vivo (Fig. 1C) or after in vitro
restimulation with SRBC in vitro (Fig. 1D).
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A). We
then investigated the implications of enhanced anti-HSV Ab
responses on the development of HSK in the
ß2m-/- mouse. Both the incidence and
severity of HSK were diminished in
B6/ß2m-/- mice compared with control B6
hosts (Fig. 2B). Since HSK is a
virally-induced autoimmune response mediated by Th1-type CD4 cells
(22), strong and early anti-HSV Ab responses may reduce the
severity of the T cell reaction to murine corneal tissue either by
decreasing viral load and/or because of a skewing toward a Th2
response.
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The above experiments suggested that ß2m-associated
suppression is normally active during in vivo Ab responses. To
determine whether suppression was dependent on class I expression and
to define the relevant lymphocyte subpopulations, an in vitro assay was
used. We analyzed the response of cultures containing B cells, CD4
cells, and CD8 cells purified from SRBC-primed mice. CD4 cells from
ß2m-/- or control mice provided equally
good help to normal B cells for the IgM response (Fig. 3
A). B cells from
ß2m-/- and control mice also produced
similar numbers of pfc when incubated with CD4 cells from either
source. However, addition of CD8 cells from SRBC-primed
(ß2m+/+) mice inhibited the response of CD4
cells and B cells by 50 to 70% (Fig. 3A). Inhibition did
not depend on whether CD4 cells were from
ß2m+/+ or ß2m-/-
donors, but was lost if B cells (and monocytes) were obtained from
ß2m-/- donors.
To determine whether CD8 suppression was dependent on ß2m
expression by B cells or macrophages, we compared highly purified B
cells with B cell depleted splenic adherent cells (SAC) from
ß2m-/- and control mice (Fig. 3B). This analysis indicated that CD8-dependent suppression
required B cells expressing ß2m-associated proteins and
that ß2m expression on SAC was not necessary for CD8
suppression (Fig. 3B). The requirement for B cells for CD8
suppression in vitro was consistent with the observation that CD8 cells
from SRBC-primed Ig-deficient mice, which lack B cells, failed to
develop suppressive activity (not shown).
Activated B cells stimulate CD8-dependent suppression in vitro and in vivo
We investigated whether B cells might act as inducer/activators of
CD8 cells or as targets of CD8 suppression. B cells were purified from
untreated mice, or mice primed with SRBC or horse RBC (HRBC) for 4
days, washed, and irradiated (2500 rad), then added
(105/well) to cultures containing
ß2m-/- B cells and CD4 cells, with CD8
cells from ß2m+/+ mice (Fig. 4A). As noted above,
suppression was not apparent in cultures containing
ß2m-/- B cells. The addition of irradiated
B cells from unprimed normal mice, or from
ß2m-/- mice, also failed to induce
suppression in these cultures (Fig. 4A). However, addition
of irradiated B cells from ß2m+/+ donors that
had been immunized with either SRBC (not shown) or HRBC induced
suppression, suggesting that activated ß2m+/+
B cells were necessary to induce CD8 suppressive activity in an
Ag-nonspecific manner. This hypothesis was confirmed by the observation
that LPS-activated B cell blasts from ß2m+/+,
but not ß2m-/- mice, also induced
CD8-dependent suppression of the RBC response (Fig. 4A).
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B). Injection of ß2m-/-
LPS-activated B cell blasts had a minor effect on the subsequent IgM
pfc response to SRBC. In contrast, injection of
ß2m+/+ LPS blasts inhibited development of
anti-SRBC by 70%. Expression of the Qa-1 molecule on activated B cells is required to induce CD8 suppression
The observation that suppression depended on
ß2m-associated molecules expressed by activated but not
resting B cells raised the possibility that nonclassical MHC molecules
were involved, since classical MHC class I is expressed at high levels
independent of activation, while levels of some nonclassical
ß2m-associated products, including Qa-1, are affected by
cell activation (23, 24). We therefore determined whether suppressor
cell activity in the SRBC system was restricted by the TL region of
mouse MHC, which includes several nonclassical class I genes that are
expressed in a tissue-specific manner. Cells from the congenic mouse
pair B6 and B6.Tlaa, which differ only at the TL/Qa region
were used in these experiments. As shown in Figure 5A, suppression only occurred
when CD8 cells and B cells were matched at the TL/Qa locus.
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B). Cultures from B6
mice, which express the Qa-1b haplotype, and
B6.Tlaa mice, which express the Qa-1a haplotype
(25), were tested for suppressive activity in the presence of
Qa-1a or Qa-1b antisera. Antiserum to
Qa-1a specifically prevented suppression in SRBC-stimulated
B6.Tlaa (Qa-1a) cultures, but not in
SRBC-stimulated B6 (Qa-1b) cultures. Conversely,
anti-Qa-1b serum blocked suppression of B6 but not
B6.Tlaa cells. Normal mouse serum (NMS) had no effect on
suppression in either case.
Potential contribution of IFN- to CD8 suppression
Activated CD8 cells might suppress the IgM response by cell-cell
interaction and/or by production of inhibitory cytokines. IFN-
produced by naive CD8 cells is known to enhance the development of Th1
cells and to inhibit Th2 responses (26). A neutralizing mAb to IFN-,
or a control mAb, was added to cultures of B cells and CD4 and CD8
cells as described above. As shown in Figure 6, CD8 suppression of the in vitro IgM
response was abrogated by addition of anti-IFN- but not by a
control mAb. In addition, inclusion of Fas-Ig did not prevent
suppression and culture of B cells, and CD8 cells from mice that harbor
the Fas lpr mutation showed similar levels of suppression as control
cells (not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-chain on Th cells
(28). In human leprosy, a CD8 suppressor cell has been described that
recognizes foreign Ag directly, and releases IL-4 to block
proliferation of Th1 cells (29).
In this report we describe a novel pathway by which suppressive CD8
cells become activated during the response to SRBC. Our data indicate
that these cells are active early in the primary response and
suppression was also apparent on the subsequent IgG pfc response. The
central finding of this study is that Qa-1 expressed on activated B
cells can induce CD8 cells to inhibit Ab responses. In contrast to
reports of suppressive CD8 cells, which recognize idiotypic
determinants of the TCR (30, 31), activation of CD8 cells via Qa-1
leads to secretion of IFN-, the major cytokine produced by CD8 cells
after primary stimulation, which may then suppress Ab responses.
IFN- together with IL-12 has been shown to inhibit the development
of both Th2 cells (32, 33) and IgM and IgG1 Ab responses (34, 35).
Although the mechanism of IFN--mediated inhibition is not fully
understood, there is evidence that it may depend on induction of
macrophage nitric oxide (34). Loss of this mechanism in
ß2m-/- mice might be expected to lead to
heightened Th2 responses and inhibition of the development of
Th1-dependent autoimmune disease (36, 37). The development of keratitis
after intracorneal infection by HSV-1 represents an example of a
tissue-specific autoimmune disease that is mediated by Th1 CD4 cells
and is inhibited by a Th2 response (36, 37). We show here that HSV
infection of ß2m-/- mice leads to both an
enhanced Th2-associated Ab response and reduced severity of keratitis
(Fig. 2).
Although little is known about the function of the Qa-1 molecule, the
available information fits well with our suggestion that it has a role
in immunoregulation. Although expressed at low levels on most cell
types, Qa-1 is expressed at higher levels on activated T and B
lymphocytes and differential expression of Qa-1 has been associated
with specialized T cell functions (13, 14, 15). Cell surface expression of
Qa-1 is reduced in Tap-1/2-deficient cells (24), indicating that
loading of Qa-1 with endogenous peptides is required for transport
through the endoplasmic reticulum and onto the cell surface. The Qa-1
3 domain contains critical residues required for interaction with
the CD8 coreceptor (24), which may allow Qa-1 to selectively present
peptides to CD8 cells, and a selective interaction between suppressive
CD8 cells and B cells may account for localization of CD8 cells to the
B cell areas of the spleen (38).
Qa-1 has a much less polymorphic structure than classical MHC class I
molecules and is unlikely to present as large an array of foreign viral
peptides. Instead, it may present a specialized subset of endogenous
peptides. The key role of B cells in this process opens the possibility
that this subset might include Ig-derived peptides that are presented
to CD8 T cells. If so, since our data indicate that the activation of
CD8 suppression is not Ag-specific (Fig. 4A), a key portion
of these putative Ig-derived peptides may be derived from the C, rather
than the V region of Ig. T cell recognition of both IgC and IgV region
peptides has been described (39, 40, 41, 42) and, in some instances, this
recognition may result in suppressive effects on the response to
Ag (43, 44).
Jiang et al. have shown that Qa-1 on CD4 cells can be recognized by CD8 cells specific for TCR-derived peptides associated with Qa-1 and that these CD8 cells can specifically kill activated T cells that express particular Vß elements (16). Our findings open the possibility that Qa-1 may play parallel roles on activated T and B cells: in both cases Qa-1 may present endogenous peptide fragments derived from the T or B cell receptor to CD8 cells during an immune response. A better understanding of the peptide-binding activity and function of nonclassical MHC class I molecules is needed to provide further insight into this mechanism of immunoregulation and T cell subset interactions.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Harvey Cantor, 44 Binney Street, Boston, MA 02115.
3 Abbreviations used in this paper: ß2m, ß2-microglobulin; HSV-1, herpes simplex virus-1; HSK, herpes stromal keratitis; SAC, splenic adherent cells; B6 mice, C57BL/6 mice; pfc, plaque-forming cells; PFU, plaque-forming unit; HRBC, horse red blood cells; NMS, normal mouse serum; PE, phycoerythrin; TL, thymic leukemia.
Received for publication May 9, 1997. Accepted for publication October 2, 1997.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and IFN- in IL-12-induced T helper cell-1 development. J. Immunol. 156:1442.[Abstract]
- and ß-chains: the Vß8+ chain dictates restriction to either K or D. J. Immunol. 145:2001.[Abstract]
modulates the early development of Th1 and Th2 responses in a murine model of cutaneous leishmaniasis. J. Immunol. 147:3149.[Abstract]
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