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*
Graduate Program in Immunology and
Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, TX 75235
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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2-microglobulin on both the B cell and
ACAID APC, but not on the T suppressor cells. Moreover, the induction
of ACAID regulatory cells required histocompatibility between the B
cells and regulatory T cells at the TL/Qa region. The results indicate
that: 1) B cells are necessary for the induction of ACAID; 2) ACAID B
cells do not directly suppress the expression of delayed-type
hypersensitivity; and 3) the induction of Ag-specific regulatory T
cells by ACAID B cells requires histocompatibility at the TL/Qa
region. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The mechanisms involved in the generation of ACAID suppressor T cells are only beginning to be elucidated. Initial findings suggest that ACAID APC present Ag in a tolerogenic manner to T cells in the spleen (7). Subsequent studies have shown that B cells are also necessary for the development of ACAID (8). Recently, it has been shown that the splenic B cell is necessary for the in vitro generation of at least one population of ACAID regulatory T cells (9). In other models of tolerance, B cells induce CD8+ suppressor T cells when peptides are presented in the context of the nonclassical class I molecule Qa-1 (10). Coupled with other studies showing that B cells can serve as tolerogenic APC (11, 12, 13, 14, 15, 16), these results suggested that the B cell might present Ag in the ACAID spleen.
The hypothesis that B cells serve as APC in the ACAID spleen requires the transportation of Ag from the eye to the spleen. Studies have shown that Ag encountered in the anterior chamber is processed and transported to the spleen by resident APC expressing the mature macrophage marker, F4/80 (17, 18). Macrophages in other sites, such as the lung and peritoneum, have the capacity to process Ag and regurgitate antigenic peptides that can be captured by a variety of cells and presented to T cells (19, 20). We postulated that this mechanism might be responsible for the delivery of peptides to B cells in the ACAID spleen. In this study, we further examined the role of the B cell in the induction of ACAID and considered the role of classical and nonclassical class I molecules on three of the key cell populations involved in the induction of ACAID—the ocular APC, the splenic B cell, and the splenic T cell
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Six- to 10-wk-old C57BL/6 and BALB/c mice were obtained from the
mouse colony at the University of Texas Southwestern Medical Center at
Dallas. B6.A-H2-T18a/BoyEg congenic mice (B6.A),
C57BL/6-Igh-6tm1Cgn B cell knockout mice,
B6.129P2-2mtm1Unc
2-microglobulin
(2m)-deficient C57BL/6 mice, and BALB/c mice
were purchased from The Jackson Laboratory (Bar Harbor, ME). BALB/c
mice transgenic for the D011.10 TCR (specific for the OVA peptide
fragment, 323–339, in the context of I-Ad
(21, 22) were kindly provided by Dr. J. Wayne Streilein
(Schepens Eye Research Institute, Harvard Medical School, Boston, MA).
All animal studies were approved by the Institutional Review Board of
the University of Texas Southwestern Medical Center at Dallas.
Preparation of peritoneal exudate cells (PECs)
PECs were collected by peritoneal lavage of mice that were injected i.p. with 2 ml of 3% thioglycolate (Sigma, St. Louis, MO) medium 3–4 days earlier.
In vitro model of the anterior chamber ("eye-in-a-dish")
In a previously described model of the anterior chamber of the
eye, TGF--treated PECs were found to mimic the function of ACAID APC
(23). PEC from normal mice were collected and suspended in
complete RPMI 1640 medium (cRPMI; JRH Biosciences, Lenexa, KS)
containing 10% FBS (HyClone Laboratories, Logan, UT), 2 mM
L-glutamine (JRH Biosciences), 10 mM HEPES buffer solution
(JRH Biosciences), 1 mM sodium pyruvate solution (JRH Biosciences), 1%
nonessential amino acids solution (BioWhittaker, Walkersville, MD), and
1% penicillin-streptomycin-fungizone solution (BioWhittaker). PEC were
incubated on plastic tissue culture dishes (Falcon 3803; Becton
Dickinson Labware, Lincoln Park, NJ) at 37°C in 5%
CO2 for 2.5 h. Plastic nonadherent cells
were washed off with HBSS (BioWhittaker). Plastic adherent cells, the
vast majority of which are macrophages (90%–95%), were collected by
gently dislodging the cells with a Nitex filter swab (Tetko, Briarcliff
Manor, NY). Our results have shown that macrophages, and not
contaminating dendritic cells, are the effector cells in this model
(data not shown). The macrophages were resuspended in cRPMI medium and
aliquoted at 1.5 x 106 cells/well in a
24-well plastic tissue culture plate (Falcon 3047; Becton Dickinson
Labware). OVA (Sigma; St. Louis, MO) was added at 5 mg/ml to each well
(24). Human rTGF-2 (Genzyme
Diagnostics, Cambridge, MA) in cRPMI was added to some wells (at 2
ng/ml). This treatment caused these cells to subsequently function as
ocular ACAID APC (25, 26). Control wells received an
identical aliquot (100 µl) of cRPMI alone (normal APC). Cell cultures
were incubated at 37°C in 5% CO2 overnight.
The next day, all cells were collected, washed with HBSS, resuspended
in cRPMI, and used in subsequent experiments.
In vitro coculture of APC with B cells
ACAID and normal APCs were prepared as described, and 3–4
x 106 cells placed into medium petri dishes
(Falcon 3002; Becton Dickinson Labware) in cRPMI. Splenocytes were
harvested and erythrocytes lysed. BALB/c B cells were isolated by
panning on plastic dishes coated with goat anti-mouse 
globulin
(ICN Pharmaceuticals, Aurora, OH) as described (8). B
cells (80–100 x 106 cells) were cocultured
with APC and incubated at 37°C in 5% CO2 for
1–2 days. The nonadherent population of cells was collected and
resuspended in cRPMI. B cells (4–5 x 106
cells) were injected i.v. into naive, syngeneic mice. In some
experiments, the nonadherent population of cells was plated on plastic
tissue culture dishes (Falcon 3803; Becton Dickinson Labware) as
described above to remove any adherent APC contaminant. Nonadherent B
cells (3–5 x 106 cells) were injected i.v.
into naive, syngeneic mice. In other experiments, the B cells were
eliminated by a standard complement lysis procedure using 10 µg/ml
rat anti-mouse B220 mAb (IgG2a; PharMingen, San Diego, CA) and 1:20
rabbit complement (Accurate Chemicals, Westbury, NY). Control
populations were treated with complement alone.
Subcutaneous inoculations
Mice were immunized by s.c. injection of OVA (125–150 µg) emulsified 1:1 in CFA (0.5 mg Mycobacterium/ml; Behring Diagnostics, Deerfield, IL) in a total volume of 100 µl.
Delayed-type hypersensitivity (DTH) assay
Seven days after s.c. immunization, both ear pinnae of experimental and control animals were measured with a Mitutoyo engineer’s micrometer immediately before challenge. OVA (400 µg) in 20 µl PBS was injected s.c. into the left ear pinnae. The right ear pinnae received 20 µl sterile PBS alone (negative control). Both ear pinnae were measured 24 h later, and the difference in ear pinnae size was used as a measure of DTH. Results are expressed as: specific ear pinnae swelling = (24 h measurement - 0 h measurement) for experimental ear - (24 h measurement - 0 h measurement) for control ear.
In vitro model of the ACAID spleen ("spleen-in-a-dish")
ACAID APC (3 x 106 cells) in cRPMI
were placed into large petri dishes (Falcon 3003; Becton Dickinson
Labware). Splenocytes were harvested and erythrocytes lysed. Whole
splenocytes (100 x 106 cells) were added to
the cultures. OVA (20 µg) was added to simulate Ag escape from the
eye in vivo. cRPMI was added to a total volume of 15 ml. The dishes
were incubated at 37°C in 5% CO2 for 7 days
with frequent agitation. B cells were isolated from the cultures by
panning on plastic dishes coated with goat anti-mouse globulin
as described above. T cells were collected in the nonadherent
population. The generation of cells capable of suppressing the
expression of DTH was assessed with a local adoptive transfer assay.
Briefly, positive immune effector T cells were generated by immunizing
BALB/c mice s.c. with OVA (250 µg) emulsified 1:1 in CFA. After 7–14
days, the spleen and peripheral lymph nodes were harvested and
erythrocytes lysed. T cells were collected by incubating the cell
suspension on scrubbed nylon wool (Fenwal Laboratories, Deerfield, IL)
at 37°C in 5% CO2 for 1 h. T cells were
eluted with 30 ml HBSS. The positive immune effector T cells were
resuspended at 108 cells/ml in 10 mg/ml OVA in
PBS. B or T cells from the spleen-in-a-dish cultures were resuspended
at the same concentration (108 cells/ml) in 10
mg/ml OVA in PBS. Equivalent volumes of positive and test cells were
mixed. Positive controls included positive immune effector T cells
mixed with naive splenocytes (108 cells/ml in 10
mg/ml OVA in PBS). Negative controls included an equivalent number of
naive splenocytes alone. Both ear pinnae of naive, syngeneic mice were
measured with a Mitutoyo engineer’s micrometer. In all cases, 20 µl
of the cell suspension (2 x 106 cells) was
injected s.c. into the left ear pinnae. The right ear pinnae received
20 µl of 10 mg/ml OVA in PBS (negative control). Both ear pinnae were
measured 24 h later, and the difference in ear pinnae size was
used as a measure of DTH due to the reactivity of the positive immune
effector T cells. A significant reduction in ear swelling was
indicative of direct suppression of this response.
Reconstitution of B cell-deficient mice
C57BL/6 wild-type and B6.A spleen cells were harvested and
erythrocytes lysed. B cells were isolated by panning on plastic dishes
coated with goat anti-mouse globulin (ICN Pharmaceuticals) as
described (8). The purified B cells were resuspended to
5 x 107 cells/ml in cRPMI, filtered through
sterile Nitex (Tetko), and 200 µl injected (107
B cells) i.v. into B cell-deficient mice. This procedure was shown to
effectively reconstitute B cell knockout mice (9).
Intracameral inoculation
Mice were anesthetized with 0.66 mg of ketamine hydrochloride
(Vetalar; Park-Davis and Co., Detroit, MI) given i.p. A glass
micropipette (
80 µm diameter) was fitted onto a sterile
infant-feeding tube (no. 5 French; Professional Medical Products,
Greenwood, SC) and mounted onto a 0.1-ml Hamilton syringe (Hamilton,
Whittier, CA). A Hamilton automatic dispensing apparatus was used to
inject 5 µl of 20 mg/ml OVA in PBS (=100 µg OVA) into the anterior
chamber via the glass micropipette.
Statistics
All experimental and control groups contained five to eight animals per group with the majority of groups having an n = 4 or 5. Differences between groups were analyzed by Student’s t test. Values of p < 0.05 were considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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If the hypothesis that tolerogenic B cells capture peptides
released by ACAID APC and present Ag to T cells is true, then one would
expect B cells to transfer ACAID. This hypothesis was tested by
coculturing ACAID APC with syngeneic B cells and transferring the B
cells into naive hosts. Briefly, ACAID and normal APCs were generated
and placed into medium petri dishes. Splenic B cells were collected as
described above and cocultured with the APC overnight. The next day,
nonadherent B cells were collected and injected (5 x
106 cells) into naive, syngeneic mice. Seven days
later, the mice were immunized s.c. with 125 µg OVA in CFA. Seven
days later, DTH was assessed. B cells cocultured with ACAID APC (ACAID
B cells) were able to transfer ACAID to naive hosts (Fig. 1
). By contrast, B cells cocultured with
normal APC (normal B cells) did not induce ACAID (Fig. 1). These data
show that ACAID APC are able to transfer an ACAID signal to splenic B
cells and support the hypothesis that B cells serve as tolerogenic APC
in ACAID.
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, ACAID B cells treated with complement
alone were able to transfer ACAID to naive mice. However, ACAID B cells
treated with anti-B220 Ab and complement were not able to induce
ACAID in naive mice (Fig. 2).
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). In summary, these results show that
the B cell is responsible for the transfer of ACAID. Moreover, they
demonstrate that ACAID APCs are able to transfer an Ag-specific
ACAID-inducing signal to B cells. This is consistent with the notion
that the signal is a peptide that can be presented by tolerogenic B
cells in the spleen.
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The results from the previous experiments strongly suggested that
the B cells induced ACAID by presenting peptides in a manner that
culminated in the generation of regulatory T cells. However, an
additional experiment was performed to rule out the possibility that
the adoptively transferred ACAID B cells were acting as direct
suppressors of DTH. We tested this possibility using a previously
described in vitro model of the ACAID spleen (9). In this
model, Ag-pulsed ACAID APCs are incubated for 5–7 days with spleen
cell cultures containing both T cells and B cells. The ensuing
nonadherent T cell population contains cells capable of suppressing the
expression of DTH (9). For these experiments, ACAID APCs
were generated and placed into culture with normal, unfractionated
spleen cells. After 7 days, the nonadherent population of cells was
collected and plated on plastic dishes coated with Ab to mouse Ig. This
procedure allowed for the separation of adherent B cells from the
nonadherent T cells. Each population was tested for the ability to
suppress the expression of DTH in a local adoptive transfer assay.
Briefly, the test population of cells was mixed with Ag (OVA) and an
equal number of OVA-primed, effector T cells. The cells were then
injected s.c. into the ear pinnae of naive mice, and ear swelling was
used as a measure of DTH. As shown in Fig. 4, the B cell population was not able to
suppress the expression of DTH. Instead, this activity was restricted
to the T cell population (Fig. 4). These data show that ACAID APCs do
not induce B cells to become direct efferent suppressors of
DTH.
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Previous studies have shown that ACAID APC do not induce ACAID
when injected into allogeneic hosts (7, 23, 26).
Accordingly, an experiment was performed to test whether MHC
restriction was important at the level of the ACAID APC interaction
with B cells. C57BL/6 and BALB/c ACAID APC were generated and placed
into culture with BALB/c splenic B cells. Two days later, plastic
nonadherent B cells were collected and injected i.v. into naive BALB/c
mice. Seven days later, all mice were immunized s.c. with 125 µg OVA
in CFA. Seven days later, DTH was assessed. As previously reported,
injection of syngeneic, but not allogeneic, ACAID APC induced
down-regulation of DTH (Fig. 5; compare
bars 2 and 3). Moreover, B cells cocultured with
syngeneic, but not allogeneic, ACAID APC induced down-regulation of DTH
(Fig. 5; compare bars 4 and 5). These results
indicate that ACAID APC cannot transfer the ACAID-inducing signal to B
cells unless the APC and B cell share the same MHC genotype.
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2m-deficient C57BL/6 mice were cultured for 2
days with OVA either in the presence or absence of TGF-. Both
categories of ACAID APC were then cultured with splenic B cells from
either normal C57BL/6 mice or 2m-deficient
C57BL/6 mice and T cells from either normal C57BL/6 mice or
2m-deficient C57BL/6 mice. After 7 days in
culture, each of the in vitro-generated regulatory T cell populations
was assessed for its capacity to suppress the expression of DTH in a
local adoptive transfer assay. Briefly, each test population was mixed
with OVA and an equivalent number of immune effector T cells. Each cell
mixture was then injected into the ear pinnae of naive mice and ear
swelling was used as a measure of DTH. The results are summarized in
Fig. 6 and demonstrate that the
development of efferent suppressor cells requires the expression of
class I molecules on both the ACAID APC and the B cells, but not on T
cells.
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The results summarized above, along with previous data, indicate
that ACAID is abrogated in mice deficient in the
2m molecule (7). Specifically,
2m knockout mice were unable to generate at
least one population of ACAID suppressor T cells. In addition to having
little to no functional class I, 2m knockout
mice do not express nonclassical class I molecules, such as Qa-1
(27, 28). Ag presentation by Qa-1 has long been known to
induce suppression of various immune responses (29, 30).
It was recently reported that B cells presenting peptide in the context
of Qa-1 induce CD8+ suppressor T cells
(10). Based on these findings, we hypothesized that B
cells generate ACAID by presenting antigenic peptides to T cells in the
context of Qa-1. Previous studies had shown that ACAID is abrogated in
B cell knockout mice and that reconstitution with normal, syngeneic B
cells restores ACAID (9). Our hypothesis was tested by
reconstituting B cell knockout mice with B cells purified from
syngeneic, B6.A congenic mice differing at the TL/Qa region
(Qa-1a). If ACAID B cells present peptide in the
context of Qa-1, then TL/Qa congenic B cells would be unable to restore
ACAID in B cell knockout mice. Splenic B cells from C57BL/6 and B6.A
mice were harvested by panning on petri dishes coated with Ab to mouse
globulin. Adherent B cells were collected and injected
(107 cells) i.v. into naive, B cell knockout
mice. Five days later, all mice were primed in the anterior chamber of
the eye with 100 µg OVA. After 7 days, all mice were immunized s.c.
with 150 µg OVA in CFA. Seven days later, DTH to OVA was assessed. As
previously described, ACAID was restored in B cell knockout mice
reconstituted with normal, C57BL/6 B cells (Fig. 7). However, ACAID was not restored in B
cell knockout mice that received B cells disparate at TL/Qa
(Qa-1a locus) (Fig. 7). FACS analysis 5 days
after reconstitution confirmed the presence of splenic B cells in these
groups (data not shown). These data provide evidence that B cells
generate ACAID suppressor T cells by presenting Ag in the context of
the nonclassical class I molecule, Qa-1.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Using the in vitro model of the ACAID spleen, we have shown that ACAID APCs can induce the generation of efferent suppressor T cells, but only if splenic cells are also present (9). We have hypothesized that ACAID APCs release antigenic peptides to B cells, which present the peptides to T cells in a manner that generates T regulatory cells. Therefore, if B cells function as tolerogenic APC in the ACAID spleen, then one would predict that B cells could transfer ACAID to naive hosts. This hypothesis was tested by coculturing ACAID APC with splenic B cells and transferring the B cells into naive hosts. The results showed that B cells could generate efferent suppressors of DTH when injected i.v. into naive, syngeneic mice. However, B cells cocultured with normal Ag-pulsed APC did not transfer ACAID. Furthermore, an in vitro model of the ACAID spleen showed that T cells, and not B cells, were directly responsible for the suppression of DTH. It was previously reported that B cells are necessary for the generation of ACAID regulatory T cells (8, 9). These results suggest that the required role of the B cell is to accept an ACAID-inducing signal from immigrant ACAID APC. We predict that this signal is a regurgitated peptide that the tolerogenic B cell presents to T cells in the ACAID spleen.
Previous data have shown that ACAID is abrogated in mice deficient in
the 2m molecule (7).
Specifically, 2m knockout mice are unable to
generate the CD8+ efferent suppressors of DTH.
The present in vitro data indicate that the generation of regulatory T
cells requires the expression of the 2m
molecule on the ACAID APC and the B cell, but not the T cell. Because
Ag presentation by the 2m-dependent,
nonclassical class I molecule, Qa-1, has been implicated in immune
regulation and the generation of CD8+ suppressor
T cells (10, 29, 30), we hypothesized that ACAID B cells
presented antigenic peptides in the context of Qa-1. The present data
show that B cells disparate at the TL/Qa region are unable to restore
ACAID in B cell-deficient mice. This suggests that B cells generate
ACAID T suppressors in the spleen by presenting antigenic peptides in
the context of the nonclassical class Ib molecule, Qa-1. This is
reminiscent of previous studies demonstrating that
Qa-1+ B cells are needed for the generation of
CD8+ regulatory T cells that inhibit Ab responses
to sheep erythrocytes (10). However, the suppression of
IgG and IgM Ab responses in that study was due to IFN- produced by
Qa-1-restricted CD8+ regulatory T cells
(10). By contrast, ACAID involves the down-regulation of
IFN- and a concomitant induction of IL-10 production
(31, 32, 33). In other systems, Qa-1-restricted
CD8+ regulatory T cells have been shown to
down-regulate Th1 immune responses and mitigate Th1-mediated autoimmune
diseases, such as experimental allergic encephalomyelitis (34, 35). Using T cell vaccination as a means of suppressing Th1
immune responses, Jiang and coworkers (34, 35) have
analyzed CD8+ regulatory T cells that
down-regulate CD4+ T responses via recognition of
Qa-1/TCR peptide complexes on the surface of CD4+
T cells. The CD4+ T cells are believed to process
and express relevant Qa-1/TCR complexes on their surface. The
CD4+ T cells express the relevant TCR peptide
coupled to Qa-1 molecules and serve as targets for cytolytic
CD8+ regulatory T cells. In this paradigm,
Qa-1/peptide complex on the CD4+ T cells acts as
a target and restricting element for CD8+
regulatory T cells. Thus, down-regulation of the immune response is
produced by deletion of the relevant CD4+ Th
cells. Experiments are underway to determine whether a similar
Qa-1-restricted cytolytic regulator cell is an integral component of
ACAID.
The present study has attempted to define the potential role of splenic B cells in the generation of ACAID suppressors of DTH. The data are consistent with the hypothesis that ACAID APC release antigenic peptides, which are preferentially or exclusively captured by splenic B cells. Moreover, B cells are able to transfer an ACAID-inducing signal to T cells, which either differentiate into efferent suppressor cells or induce the generation of suppressor T cells. In this regard, it is noteworthy that Sonoda et al. (36) have demonstrated that CD1-reactive NKT cells are needed for the development of efferent suppressor cells of ACAID. Interestingly, the APCs in the spleen that express the highest density of CD1 are the marginal zone B cells (37).
The present findings also demonstrate that the expression of class I, specifically Qa-1, on splenic B cells is necessary for the induction of ACAID. It will be important to show that the mechanism of peptide transfer is directly involved in the development of ACAID. Moreover, it is not known how the B cells capture peptide or whether the peptide is reprocessed in the B cell. We have previously demonstrated that B cells are necessary for the induction of ACAID to alloantigens. Accordingly, it will be critical to determine whether Qa-1 plays a role in the processing of alloantigens and other soluble Ags that are known to induce ACAID. Nevertheless, these data suggest a mechanism in which resident ocular macrophages process Ag in the eye and migrate to the spleen, where they transfer the relevant peptide moiety to B cells in a class I-restricted, Qa-1-dependent manner.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Jerry Y. Niederkorn, Department of Ophthalmology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9057.
3 Abbreviations used in this paper: ACAID, anterior chamber-associated immune deviation; DTH, delayed-type hypersensitivity; 2m, 2-microglobulin; PEC, peritoneal exudate cells; cRPMI, complete RPMI 1640; HEL, hen egg lysozyme.
Received for publication July 31, 2000. Accepted for publication September 27, 2000.
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0.0003 for MHC
mismatch and allogeneic ACAID APC vs negative control.
