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T Cells Are Needed for Ocular Immune Privilege and Corneal Graft Survival1
*
Graduate Program in Immunology and
Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, TX 75390
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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T cells play a major role in other forms of immune regulation, we
suspected they might contribute to the induction and expression of
ACAID. Mice treated with anti- Ab failed to develop ACAID
following anterior chamber injection of either soluble Ag (OVA) or
alloantigens (spleen cells). Additional experiments with knockout mice
confirmed that mice lacking functional T cells also fail to
develop ACAID. Using a local adoptive transfer of DTH assay, we found
that T cells were required for the generation of regulatory T
cells, but did not function as the efferent regulatory cells of ACAID.
The importance of T cells in corneal allograft survival was
confirmed by blocking T cells with GL3 Ab before corneal
transplantation. While in vivo treatment with normal hamster serum had
no effect on corneal graft survival, infusion of anti- Ab
resulted in a profound increase in corneal allograft rejection. Thus,
T cells are needed for sustaining at least one aspect of ocular
immune privilege and for promoting corneal allograft
survival. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and MIF throughout the eye and in the
aqueous humor (5, 6, 7, 8), limited expression of MHC class I
and II molecules (9, 10, 11, 12), and the expression of
nonclassical class I molecules on ocular cells possessing poor
regenerative capacities (13). Dynamic regulatory
mechanisms also contribute to the immune privilege of the eye. Ags
introduced into the anterior chamber elicit a deviant systemic immune
response, termed anterior chamber-associated immune deviation
(ACAID),3 in which
potentially injurious immune effector mechanisms, such as delayed-type
hypersensitivity (DTH) and complement-fixing Abs, are suppressed. The exact mechanisms involved in the induction of ACAID are poorly understood. However, Streilein and coworkers (14, 15, 16, 17, 18) have offered compelling evidence that APCs in the eye capture intraocular Ags and migrate to the spleen, where they induce at least two functionally distinct regulatory T cell populations in the ACAID spleen. One population is CD4+ and blocks the induction or afferent component of the immune response. A second population is CD8+ and inhibits the expression of DTH by previously sensitized T cells. In addition to ocular APCs, the generation of both populations of ACAID regulatory cells requires the participation of splenic B cells and NKT cells (19, 20, 21). The cellular interactions between B cells, NKT cells, and splenic regulatory T cells have not been elucidated, and it is possible that additional accessory cells are needed for the generation of ACAID.
T cells represent a small population of lymphocytes that are
typically CD4-/CD8-.
However, CD8+ T cells have been reported
(22). A variety of functions have been ascribed to
T cells. T cells have been shown to play a role in other forms
of tolerance, including oral tolerance (23, 24, 25),
testicular tolerance (26), and tumor-associated tolerance
(27, 28, 29). Considering their role in various forms of
immune tolerance, we entertained the hypothesis that T cells
were necessary for the induction of ACAID.
In this study, we report that T cells are required for the
induction of ACAID. Because ACAID can be induced by a variety of Ags
(30, 31, 32, 33), we examined the role of T cells in
generating ACAID to a soluble Ag, as well as to a particulate Ag. We
also demonstrate that T cells are needed for the generation of
efferent suppressors, but are not actually efferent suppressors
themselves. Finally, because ACAID has been shown to be necessary for
orthotopic corneal graft survival in the mouse (34, 35, 36),
we also examined whether T cells were needed for corneal graft
survival. Our experiments utilized anti-TCR -chain Ab, GL3,
first described by Goodman and Lefrancois (37). This Ab
inhibits the function of T cells by blocking the TCR -chain
(25).
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Six- to 10-wk-old BALB/c mice were obtained from the mouse
colony at the University of Texas Southwestern Medical Center at
Dallas. C57BL/6, NZB, BALB/c x C57BL/6 F1
(CB6F1) BALB.B, and TCR -chain knockout mice (TCR KO)
(C57BL/6J-Tcrdtm1 Mom) were obtained from The Jackson Laboratory (Bar
Harbor, ME). GL3 Ab was produced from hybridoma cells and purified by
protein A columns. The hybridoma was graciously provided by Dr. Leo
Lefrancois (University of Connecticut, Farmington, CT). Animals treated
with GL3 Ab or normal hamster serum (N.S.) for ACAID experiments were
dosed i.p. with 200 µg on days -3, +4, and +11. Animals treated with
GL3 Ab or normal hamster serum for corneal transplantation were dosed
i.p. with 200 µg two times each week starting at day -7. All animal
studies were approved by the Institutional Review Board of the
University of Texas Southwestern Medical Center at Dallas. UC-7 is an
anti- Ab (PharMingen, San Diego, CA). FITC GL3 Ab
(PharMingen) was used in FACS staining. Armenian hamster serum was
purchased from Cytogen Research and Development (West Roxbury,
MA).
Induction of ACAID
ACAID was induced as described previously using microinjection of Ag into the anterior chamber of the eye (38). Briefly, mice were anesthetized with 0.133 mg/Kg ketamine hydrochloride (Fort Dodge Laboratories, Fort Dodge, IA) and 0.006 mg/Kg xylazine (Bayer, Shawnee Mission, KS) given i.p. A glass micropipette (approximately 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 (Hamilton, Whittier, CA) syringe. A Hamilton automatic dispensing apparatus was used to inject 5 µl of the 20 mg/ml OVA (Sigma, St. Louis, MO) in PBS (100 µg OVA) or 5 µl of the 2 x 108 cells/ml (NZB or BALB.B) nonadherent spleen cells in HBSS (1 x 106) into the anterior chamber.
Nonadherent spleen cells
Splenocytes from naive mice were harvested and the erythrocytes were lysed. Each spleen was resuspended in 5 ml complete RPMI and placed in a Primaria petri dish (Becton Dickinson Labware, Franklin Lakes, NJ). The splenocytes were incubated for 2 h at 37°C in 5% CO2. The nonadherent cells were drawn off carefully. Other nonadherent cells were collected by gentle swirling after 5 ml cRPMI was added to the side of the dish.
Subcutaneous inoculations
Mice were immunized by s.c. injection of either OVA in PBS (125–250 µg) or 1 x 106 (NZB or BALB.B) spleen cells in HBSS emulsified 1:1 in CFA (Sigma). Each animal received a total volume of 200 µl.
DTH assay
Both ear pinnae of experimental and control animals were
measured with a Mitutoyo engineer’s micrometer immediately before
challenge. For OVA experiments, OVA (400 µg) in 20 µl PBS was
injected intradermally into the left ear pinnae. For alloantigen
experiments, -irradiated (3000 rad) NZB or BALB.B spleen cells
(4 x 106) were injected intradermally into
the left ear pinnae. The right ear pinnae received 20 µl sterile PBS
alone (negative control). Both ears were measured 24 h later, and
the difference in size was used as a measure of DTH. Results were
expressed as: specific ear swelling = (24-h measurement -
0-h measurement) for experimental ear - (24-h measurement -
0-h measurement) for negative control ear.
Depletion of T cells
C57BL/6 splenocytes were collected and erythrocytes were lysed.
Splenocytes were incubated with UC7 Ab (5
µg/107 cells) for 30 min on ice. The cells were
washed three times thoroughly with HBSS. The cells were then incubated
with Low-Tox rabbit complement (Accurate Chemical, Westbury, NY) (1:10)
for 30 min at 37°C and 5% CO2. Depletion of
T cells was verified by FACS analysis using FITC-conjugated GL3
Ab. Splenic T cell population fell from 3.2% to 0.9% following
Ab treatment.
Assay for assessing DTH regulatory cells
Regulatory cells were generated by injecting OVA into the anterior chamber on day 0 (see above). These animals were also s.c. immunized on day 7 with OVA in CFA (see above). Spleen cells containing the regulatory cells were collected on day 14. Erythrocytes were lysed and the cells were resuspended at 5 x 107 cells/ml in 10 mg/ml OVA in PBS. Preimmune cells were generated by s.c. immunizing naive C57BL/6 mice on day 0 with OVA (250 µg) in PBS emulsified in CFA. Splenocytes were collected on day 14, erythrocytes lysed, and the splenocytes were passed over nylon wool to enrich for T cells. The preimmune T cells collected from the nylon wool column were resuspended at 5 x 107 cells/ml in 10 mg/ml OVA. The preimmune and regulatory cell populations were mixed 1:1 and injected into the left ear pinna (20 µl = 1 x 106) of a naive C57BL/6 mouse. The opposite ear was injected with 10 mg/ml OVA as a negative control. Ear swelling was measured 24 h later.
Orthotopic corneal transplantation
Penetrating orthotopic corneal transplants were performed as described previously (39, 40). NZB mouse corneas were transplanted (2.5 mm diameter) orthotopically onto the graft beds (2 mm in diameter) of naive or GL3-treated CB6F1 mice. Proparacaine HCl ophthalmic solution (USP (0.5%); Alcon Laboratories, Ft. Worth, TX) was used as a topical anesthetic. Vannas scissors were used to excise the corneas. Donor corneas were sewn onto the graft bed using 11-0 nylon sutures (Ethicon, Somerville, NJ). Sutures were removed on day 7 posttransplantation. Topical antibiotic (Bacitracin zinc and polymyxin B sulfate; Akorn, Decatur, IL) was applied immediately after surgery, as well as immediately after suture removal. Grafts were read two times each week using a slit-lamp (Carl Zeiss, Jena, Germany). Corneas were scored using a scale of 0–4 for opacity, edema, and vascularity (41). Two consecutive opacity scores of three or higher indicated graft rejection. No immunosuppressive drugs were applied topically or systemically.
Statistics
The student’s t test was used to evaluate the
significance of these experiments. 
2 analysis was
used to test the graft survival data. p values less than
0.05 were considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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T cells are needed for the generation of ACAID to
soluble Ag
ACAID can be generated using a variety of Ags, including the
soluble Ag OVA. To induce ACAID, mice were injected intracamerally
(i.c.) with OVA on day 0. On day 7, the i.c. primed animals were
injected s.c. with OVA in PBS emulsified in CFA, and 1 wk later animals
were challenged by intradermal injection of OVA. Positive controls were
s.c. immunized with OVA in CFA 7 days before ear challenge. Negative
controls were simply challenged with OVA in the ear. Ear swelling was
used to assess the presence of DTH. Animals injected with OVA i.c. had
decreased ear swelling, indicating the presence of ACAID. To test
whether T cells affected the ability of OVA to generate ACAID,
we first treated BALB/c mice with 200 µg GL3 on days -3, +4, and +11
to block the TCR -chain of T cells (25). These
animals were then tested for their ability to develop ACAID to OVA.
Mice treated with GL3 Ab were unable to induce ACAID, as seen by their
inability to suppress DTH to OVA (Fig. 1
). In contrast, mice treated with an
isotype control serum developed ACAID.
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T cells are needed for the generation of ACAID to
alloantigens
OVA is an example of a soluble Ag that can induce ACAID, but
alloantigens can also be used to induce ACAID. We wanted to test
whether GL3 treatment blocked ACAID to alloantigens. As before, animals
were treated on days -3, +4, and +11 with 200 µg GL3 Ab. In these
experiments, NZB nonadherent spleen cells were used as alloantigens for
the induction of ACAID. Allogeneic NZB splenocytes were injected i.c.
on day 0 into normal CB6F1 mice, as well as
GL3-treated CB6F1 mice. This donor-host
combination shares the same MHC haplotype, but is mismatched at
multiple minor histocompatibility loci. On day 7, these animals, as
well as the positive controls, were s.c. immunized with NZB spleen
cells in HBSS emulsified in CFA. On day 14, the mice were challenged
with intradermal injections of irradiated (3000 rad) NZB spleen cells.
The absence of significant ear swelling indicated the presence of ACAID
in untreated mice. However, animals treated with GL3 Ab showed
significant ear swelling, and thus, did not develop ACAID (Fig. 2).
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KO animals cannot induce ACAID to soluble Ag
To ensure that the GL3 Ab was indeed blocking the T cells,
rather than stimulating them, we used TCR KO mice to test for their
ability to develop ACAID to OVA. Because TCR KO mice are on a
C57BL/6 background, the experiments were performed in C57BL/6 animals.
As before, naive C57BL/6 and TCR KO mice were injected i.c. with OVA
on day 0. On day 7, the i.c. primed animals and positive control
animals were injected s.c. with OVA in PBS emulsified in CFA. One week
later, animals were challenged by intradermal injection of OVA in PBS.
Ear swelling was measured to detect the presence of DTH. The absence of
ear swelling indicated the presence of ACAID in wild-type C57BL/6 mice
primed in the anterior chamber with OVA (Fig. 3). In contrast, TCR KO mice were
unable to suppress DTH to OVA, indicating the absence of ACAID.
Therefore, T cells are needed for ACAID. This supports the
observation that GL3 Ab blocked T cells, in vivo, and therefore
inhibited the generation of ACAID.
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KO mice
In the above experiments, the animals with impaired T cell
function are compared with control mice that have intact T cell
function. We performed additional experiments to address the
possibility that mice with impaired T cell function may display
an exaggerated DTH relative to the wild-type animals. In these
experiments, we induced ACAID by i.c. injecting KO animals on
day 0. On day 7, the i.c. injected mice, as well as the knockout
positive controls, were s.c. immunized with Ag. Finally, on day 14, all
groups, including the KO negative controls, were challenged with
Ag in the ear pinnae. Animals tested with soluble OVA Ag (Fig. 4a), as well as those tested
with BALB.B alloantigen (Fig. 4b), confirmed earlier
results, and demonstrated that the positive KO controls did not
display an exaggerated DTH response.
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T cells are not efferent suppressor cells
Earlier studies have shown that there are two populations of T
cell suppressors in the ACAID spleen, CD4+
afferent suppressor cells and CD8+ efferent
suppressor cells (14). Moreover, we have independently
confirmed that the efferent suppressors are a TCR
+CD4-CD8+
T cell using the same LAT assay described below (data not
shown). Because some T cells are CD8+
(22), it is possible that the efferent suppressors are
CD8+ T cells. To test this hypothesis,
ACAID spleens were tested for their ability to suppress the expression
of a preexisting immune response in the absence of T cells. The
assay for efferent suppression was a local adoptive transfer assay in
which ACAID efferent regulatory cells were generated using OVA as the
Ag. The spleen cells, containing the putative efferent suppressors,
were collected on day 14. These efferent suppressors were either used
directly, or were first depleted of T cells using UC7 Ab plus
complement. Preimmune splenocytes were generated independently by s.c.
immunizing naive C57BL/6 mice with OVA. On day 14, immune spleen cells
were isolated, enriched for T cells, and mixed with Ag and the ACAID
efferent regulatory cells. This inoculum was injected directly into the
ear pinnae of naive C57BL/6 mice. If T cells were acting as
efferent suppressor cells, removing them from the suppressor cell
population would inhibit the down-regulation of DTH. However, as seen
in Fig. 5, eliminating T cells
from the suppressor cell population did not have an effect on the
suppression of DTH, and therefore did not affect the expression of
ACAID.
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T cells are needed for the generation of ACAID efferent
suppressors
Although T cells did not function directly as efferent
suppressors in ACAID, they might play a role in the generation of ACAID
efferent suppressor cells. To test this hypothesis, we attempted to
generate efferent suppressor cells in KO mice. As previously
shown, these animals do not have T cells, and do not develop
ACAID. In these experiments, naive C57BL/6 mice, as well as TCR KO
mice, were injected i.c. with OVA on day 0. These animals were s.c.
immunized on day 7 with OVA in CFA, and potential ACAID suppressor
cells were isolated on day 14. Preimmune splenocytes were generated
independently by s.c. immunizing naive C57BL/6 mice on day 0 with OVA
in CFA. On day 14, preimmune splenocytes were isolated and enriched for
T cells. The ACAID regulatory cells were mixed with Ag and the
preimmune T cells then injected intradermally into the ear pinnae of
naive C57BL/6 mice. The results in Fig. 6
indicate that the absence of T cells prevented the generation of
efferent suppressors in response to i.c. OVA priming.
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T cells are needed for corneal graft survival
A growing body of evidence suggests that the high success rate of
orthotopic corneal allografts is due to the corneal graft’s capacity
to induce ACAID to the donor’s minor histocompatibility Ags (35, 36). Since T cells are needed for the induction of ACAID,
we suspected that they were also necessary for orthotopic corneal
allograft survival. Accordingly, NZB corneas were grafted
orthotopically to CB6F1 hosts that were treated
with either GL3 Ab or normal hamster serum. Untreated
CB6F1 mice served as the normal control and
received orthotopic NZB corneal allografts. Other hosts were treated
with either GL3 Ab or normal hamster serum 7 days before corneal
transplantation and twice per week thereafter until day 50. The results
in Fig. 7 indicate that treatment with
anti- Ab had a profound effect on corneal allograft survival.
Corneal allografts underwent rejection in only 20% of the untreated
mice and 0% of the mice treated with normal hamster serum. By
contrast, 75% of the corneal grafts underwent rejection in the
anti--treated mice. Thus, T cells appear to play a
crucial role in the survival of corneal allografts in this donor-host
combination.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(43) that has been shown to be important in ACAID
(44, 45). The role of B cells and NKT cells in ACAID is
not fully understood. However, the studies performed have shown that
these cell types are needed for the generation of the efferent
suppressor cells that are ultimately responsible for the decreased DTH
phenotype.
Our results suggest that yet another accessory cell, the T cell,
is required for the induction of ACAID. We demonstrate that T
cells are needed for the induction of ACAID to soluble Ag, as well as
particulate Ag. Furthermore, the T cells are not the
CD8+ efferent suppressor cells themselves, but
are needed for their generation.
T cells play an important role in various forms of immune
tolerance, and are present at the maternal-fetal interface, an
immunologically privileged site (46). The induction of
oral tolerance to OVA requires an intact T cell population.
Also, T cells are needed in orally induced tolerance to
experimental autoimmune uveitis (23). Additionally,
Szczepanik and coworkers (47) demonstrated that in a high
dose Ag-induced tolerance model, T cells down-regulated IFN-
production by immune effector T cells, and inhibited contact
hypersensitivity responses in immune animals. Finally in mouse tumor
models, T cells act to inhibit the generation of cytotoxic NK
cells and CTLs, presumably through their secretion of the
immunosuppressive cytokines IL-10 and TGF- (29).
We are attracted to the hypothesis that T cells act as ancillary
cytokine-producing cells to create an environment that is conducive to
the induction of ACAID. It is noteworthy that T cells produce
biologically significant quantities of two cytokines, IL-10 and
TGF-, which are crucial for the induction and expression of ACAID
(29). Moreover, T cells can inhibit the production
of IFN-, a cytokine that is closely associated with the
abrogation of ACAID (45, 47, 48, 49). Potentially, the
T cells are contributing to the generation of ACAID efferent
suppressors by generating cytokines critical for the ACAID environment
of the spleen.
Our results suggest that the role of T cells is to inhibit the
generation of efferent suppressor cells. The efferent suppressors are
the cells that define the decreased DTH phenotype of ACAID, and there
are many cells that orchestrate their production. The T cells
may not directly influence the CD8+ efferent
suppressors, but rather affect some of the other spleen cells involved
in generating the ACAID phenotype. For example, T cells can
inhibit the proliferation of CD4+ T cells
(50), thus eliminating potential DTH-causing lymphocytes,
and allowing for the development of efferent suppressors. This is
further supported by evidence that T cells can decrease the
ability of T cells to induce contact sensitivity
(47), a DTH response.
We and others have demonstrated that ACAID has a profound effect in
promoting corneal allograft survival (34, 35, 36). Therefore,
if T cells contribute to ACAID and thus, corneal allograft
survival, depleting T cells should promote corneal graft
rejection. This in fact was the case, as systemic treatment with Ab to
T cells had a deleterious effect on corneal allograft survival.
The normal rejection rate for NZB corneal allografts on
CB6F1 hosts is only 20%. However, rejection rose
to 86% in hosts treated with anti- T cell Ab. These results
further emphasize the importance of ACAID in promoting corneal
allograft survival.
In summary, we have shown that T cells are needed for the
generation of ACAID to soluble alloantigen. TCR KO animals cannot
generate ACAID, and T cells are needed for the generation of
efferent suppressors, but are not efferent suppressors themselves.
Finally, because ACAID is needed for corneal graft survival, abrogating
ACAID by blocking T cells could be the cause of decreased
corneal graft survival. These results reveal yet another role for the
T cells in tolerance, and another cell population needed for the
generation of ACAID.
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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; i.c., intracamerally; KO, knockout; MIF, macrophage migration-inhibitory factor; LAT, local adoptive transfer.
Received for publication September 22, 2000. Accepted for publication January 19, 2001.
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, p = 0.003 for negative vs positive control.
, p = 0.01 for i.c. injected vs negative
control. Each group represents five animals. Each experiment was
performed one time.
