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Department of Pathology and Immunology and Center for Immunology, Washington University School of Medicine, St. Louis, MO 63110
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-chains inhibit diabetes transfer. The clonotype-low
CD4 T cells appear late in the ontogeny in the thymus and peripheral
lymphoid organs, coinciding with resistance to cyclophosphamide-induced
diabetes. These results demonstrate that diabetic processes in NOD.BDC
mice are regulated by a balance between diabetogenic T cells and
regulatory T cells. In the absence of specific manipulation, regulatory
T cell function seems to be dominant and mice remain diabetes free.
Understanding of mechanisms by which regulatory T cells inhibit
diabetogenic processes would provide means to prevent diabetes
development in high-risk human populations. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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cells (1). The
nonobese diabetic (NOD) mouse develops spontaneous IDDM that shares
many of the key features of the human disease (2) and is
an excellent small animal model to dissect the pathogenesis of IDDM.
The disease is primarily mediated by T cells recognizing pancreatic
cell Ags (3, 4, 5). However, in the initial phase of the
disease, macrophages, B cells, and T cells infiltrate the pancreatic
islets without destroying the cells (2). After a
gradual increase in the cellular infiltrate, termed insulitis, the
progressive destruction of cells takes place, leading to a complete
loss of insulin production and dysregulation of glucose metabolism.
Although the course of human IDDM development cannot be studied
systematically, there are ample observations suggesting that similar
progression of immune destruction of pancreatic cells takes place
in human IDDM (1). Susceptibility to the development of IDDM has a strong linkage to certain class II MHC genes both in humans and mouse (6, 7). However, environmental factors also play an important role in the development of IDDM. This is most clearly evident from the concordance of disease development in identical twin studies (8), which is <50%. Although there are no known factors for the regulation of diabetes development in humans, numerous factors that include infection with bacteria and virus and external manipulations, such as immunization with CFA and cyclophosphamide (CY) injection, influence diabetes development in NOD mice (9, 10).
Recently, it has been suggested that T cells bearing a unique surface
marker and/or expressing a unique surface receptor play an important
role in down-regulating autoimmune responses (11, 12, 13).
These are either CD25+CD4+
regulatory T cells (11) or nonpolymorphic TCR
(V14 for mouse and
V24 for humans) positive NK T cells (13, 14). Both cell types, under certain experimental conditions, are
capable of regulating a diabetogenic process (13, 15).
However, the role of these T cells in the natural course of diabetes
development as well as in the protection of diabetes by external
manipulations remains unclear. Studies of the precise cell-cell
interactions and the effect of environmental factors during diabetes
development/protection has been difficult due to the heterogeneity of
the cell types present in vivo.
Transgenic mice carrying TCR genes from an islet Ag-specific CD4 T cell clone (BDC2.5) were established by Mathis and Benoist in the B6 x SJL F2 background (16) and backcrossed to NOD mice (from here on referred to as NOD.BDC mice). In the early stages of backcrossing, the transgene-positive mice showed high penetrance and an accelerated development of diabetes (16). However, after extensive backcrossing to NOD mice, the incidence of diabetes in NOD.BDC transgenic mice decreased drastically. Mathis and Benoist’s group demonstrated that genetic elements derived from B6 mice were responsible for the early development of diabetes in BDC TCR transgenic mice (17). T cells bearing BDC 2.5 TCR were still diabetogenic, since mice carrying a monoclonal T cell population (NOD.BDC mice on the NOD.SCID background) developed diabetes very rapidly (18). Furthermore, several external factors, including CY, induced diabetes in NOD.BDC mice more rapidly than in normal NOD mice (19). The diabetogenic T cells seem to be suppressed by cells present in NOD.BDC but not in NOD.BDC.SCID mice. Thus, the NOD.BDC mouse serves as an excellent model to examine the interactions between defined diabetogenic T cells and other cell types for the regulation of diabetes development in vivo.
The major obstacle in examining the cellular interaction in normal NOD.BDC mice has been the lack of an appropriate reagent that can distinguish diabetogenic BDC2.5 TCR-bearing T cells from other T cells. To overcome this problem, we generated a B cell hybridoma that produces an Ab specific to the BDC2.5 TCR. Using this mAb, we examined the interactions between diabetogenic T cells and regulatory T cells in NOD.BDC mice.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The BDC 2.5 TCR transgenic mice on the NOD background (NOD.BDC, 13 generations backcrossed to NOD) and NOD.SCID background (NOD.BDC.SCID) were established in our mouse colony at Washington University Medical School. Normal NOD and NOD.SCID mice were obtained from The Jackson Laboratory (Bar Harbor, ME) and maintained in our mouse colony at Washington University Medical School.
Production of hybridoma-producing anti-TCR Ab
A hybridoma cell line producing Ab specific for the BDC2.5 TCR was established by the method described previously (20). Briefly, BALB/c mice were immunized with BDC2.5 T cell line (1 x 107) i.p. four times at 2-wk intervals. Four weeks after the last immunization, mice were boosted with the same number of T cells i.v. and 3 days later the spleen cells were fused to a myeloma cell line. Hybridoma supernatants were tested for the capacity to stimulate BDC 2.5 T cells to produce IL-3. One hybridoma cell line, aBDC, producing an IgG2b Ab was established and cloned twice under limiting dilution conditions. The Ab was purified and biotinylated for the experiments.
Immunofluorescence analysis
Surface immunofluorescence analysis of thymocytes, lymph node
cells, and T cell clones was performed as described previously
(21). In brief, T cell clones were incubated with aBDC Ab
for 30 min at 4°C, washed, and reincubated with FITC-conjugated goat
anti-mouse IgG Ab. For two-color surface immunofluorescence, cells
were incubated with rat Ab specific for Thy1 (AT83), CD4 (GK1.5), or
CD8 (3.155) for 30 min at 4°C, followed by incubation with
FITC-conjugated goat anti-rat IgG. The cells were counterstained
with none, biotinylated anti-V4 Ab (KT4),
or biotinylated aBDC Ab followed by avidin-PE. For three-color
staining, cells were incubated with PE-anti-CD4, FITC-anti-CD8,
and biotin-labeled aBDC Ab for 30 min at 4°C, washed, and further
incubated with streptavidin-RED613 (Life Technologies, Rockville, MD).
For the analysis of CD25 expression, cells were stained with
FITC-anti-CD4, PE-anti-CD25 (7D4), and biotinylated aBDC Ab
followed by streptavidin-RED613. Stained cells were analyzed by a
FACSCalibur analyzer using the CellQuest program (BD Biosciences,
Mountain View, CA). PE- or FITC-labeled anti-CD4, FITC-labeled
anti-CD8, and PE-labeled anti-CD25 Abs were purchased from BD
PharMingen (San Diego, CA). Other Abs were purified and biotinylated in
our laboratory.
T cell proliferation assay
Lymph node cells were treated with anti-CD8 Ab (3.155: rat
IgM Ab) plus complement. Aliquots of cells were stained with
biotinylated anti-CD4 Ab followed by avidin-PE. CD4-positive T
cells were sorted based on their idiotype expression using a
FACSVantage sorter (BD Biosciences). Pancreatic cells were prepared
from B10.BR mice by the methods described previously. Cells (2.5
x 105 irradiated NOD spleen cells and indicted
NOD.BDC responding cell populations) were cultured with irradiated
(2000 rad) pancreatic cells in a final volume of 200 ml 5%
FCS/DMEM in flat-bottom microtiter plates. After 72 h of
incubation with a 6-h pulse with [3H]thymidine,
cultures were harvested for counting.
CY-induced diabetes
Mice received 200 mg/kg CY on days 0 and 14 and were monitored for the development of diabetes. Mice with high blood glucose on day 14 did not receive a second CY injection.
Cell transfer
Transfer of diabetes by spleen cells was conducted by the method described previously. In brief, NOD.SCID mice receive either nonfractionated spleen cells, cells sorted based on their surface phenotype, or a mixture of two different populations of cells. For an enrichment of cell populations based on their expression of CD4 and clonotype, cells were stained with anti-CD4 Ab and aBDC Ab as described above and sorted for the clonotype-high and clonotype-intermediate CD4-positive populations using a FACSVantage cell sorter. Mice were monitored for the development of diabetes for 5 wk.
Diabetes
Mice were monitored for the development of diabetes by measuring urine glucose with Diastix strips (Miles, Madison, WI) twice a week. Mice with glucosuria were tested for the blood glucose level and those showing >250 mg/dl of blood glucose two consecutive reading in a week were considered diabetic.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The aBDC Ab only reacted with BDC 2.5 T cells but not with six
other independent Ag-specific CD4 T cell clones derived from NOD mice
(a representative result with an OVA-specific T cell clone is shown in
Fig. 1
A). Lymph node cells
from NOD.BDC mice and control NOD mice were stained with anti-Thy1
Ab and counterstained with either anti-V4
Ab or aBDC Ab. As shown in Fig. 1B, T cells from NOD.BDC
mice were stained uniformly with anti-V4
Ab, while only a fraction of T cells from normal NOD mice were positive
with the same Ab. Staining of lymph node T cells from NOD.BDC mice with
aBDC Ab was heterogeneous with high, low, and no staining populations.
There was no aBDC Ab staining of T cells from normal NOD mice. Thus,
aBDC Ab shows all of the characteristics of an anti-idiotypic Ab
for BDC2.5 TCR.
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Using aBDC Ab, the expression of BDC2.5 TCR was examined in both
CD4 and CD8 single-positive T cell populations from young (8-wk-old)
and old (25-wk-old) NOD.BDC mice. As shown in Fig. 2A, the T cell population from
young NOD.BDC mice contains predominantly CD4-positive cells (41% CD4
and 7% CD8). Total number as well as percentage of CD8-positive T
cells increased in old NOD.BDC mice (32% CD4 and 17% CD8). CD4 T
cells from both young and old mice were stained uniformly with
anti-V4 Ab. However, staining with aBDC Ab
showed age-dependent changes for the presence of clonotype-low and
-negative populations (Fig. 2B). In young mice, very few T
cells stained weakly with aBDC Ab, while there were significant numbers
of clonotype-negative and -low populations of CD4-positive T cells from
old mice. In contrast, CD8 T cells from both young and old mice stained
uniformly with anti-V4 and aBDC Abs.
However, staining intensity with anti-V4
Ab was significantly higher than that with aBDC Ab, similar to
clonotype-low CD4 T cell populations in old mice. These clonotype-low T
cells (both CD4 and CD8 populations) are very likely expressing both
transgene-derived and endogenous TCR -chains that associate with the
transgenic -chain.
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). All control
NOD mice (12 wk old) developed diabetes after a second CY treatment.
Thus, old NOD.BDC mice were more resistant to CY-induced diabetes than
young NOD.BDC or normal NOD mice.
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). However
idiotype-high CD4 T cells from old mice exhibited strong proliferation.
In contrast, idiotype-intermediate CD4 T cell showed no proliferative
response but exhibited a strong inhibitory effect on the proliferation
of idiotype-high CD4 T cells (Fig. 3). Taken together, these results
demonstrate a correlation between the appearance of
clonotype-low/negative CD4 T cells, decreased islet Ag reactivity, and
resistance to CY-induced diabetes development.
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Analysis of NOD.BDC mice at different ages revealed that 12- to
18-wk-old mice were very heterogeneous for the number of
clonotype-low/negative CD4 T cells. Taking advantage of this
heterogeneity, we examined further the relationship between the
presence of clonotype-low/negative CD4 T cells and
susceptibility/resistance to CY-induced diabetes. Twelve-week-old
NOD.BDC mice were treated with CY and the development of diabetes was
monitored for 14 days. These mice exhibited heterogeneity for the
CY-induced diabetes development (four of seven mice developed diabetes;
data not shown). Clonotype expression in CD4-positive T cells was
analyzed in the mice that developed diabetes and those that remained
free of diabetes. CD4 T cells from nondiabetic mice contained a
significant number of clonotype-low populations, while T cells from
diabetic mice contained almost no clonotype-low populations
(representative results are shown in Fig. 4; in diabetic mice all
V4-positive T cells are stained with aBDC Ab,
whereas in nondiabetic mice 20% of
V4-positive T cells are either clonotype low
or negative). It should be noted that both mice had significantly
increased numbers of lymph node and spleen cells due to the rebound
after CY treatment. This increase was found in all components of
splenic and lymph node cells including CD4 T cells. These results again
strongly indicate that clonotype-low/negative populations are
responsible for the protection of NOD.BDC mice from CY-induced diabetes
development.
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To test directly the function of clonotype-low CD4 T cells for the
inhibition of diabetes development, we used a cell transfer model. As
shown in Table II, total spleen cells
from NOD.BDC (25-wk-old) mice did not transfer diabetes efficiently
(only 1 of 10 recipients became diabetic), whereas as few as 5 x
105 sorted CD4 T cells with high expression of
clonotype transferred diabetes in all mice tested. CD4 T cells from
NOD.BDC mice expressing intermediate and no clonotype marker did not
transfer diabetes. However, when clonotype-intermediate CD4 T cells
were mixed with diabetogenic clonotype-high CD4 T cells for disease
transfer, recipient mice remained diabetes free. There was no
inhibition of diabetes by the same number of CD4-positive T cells from
normal prediabetic NOD mice. Thus, it seems that clonotype-intermediate
CD4 T cells have a potent inhibitory capacity over that of
nonfractionated CD4-positive T cells from normal NOD mice. When these
idiotype-high and -intermediate CD4 T cells were analyzed for the
expression of CD25, a marker for regulatory T cells (Fig. 5), although there is some difference
between these two populations for the expression of CD25, the vast
majority of CD4 T cells in both idiotype-high and idiotype-low
populations were negative for the expression.
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It has been shown that the
CD4+CD25+ regulatory T
cells are generated in the thymus in an age-dependent manner. Clonotype
expression of the thymic CD4 single-positive T cells was examined using
8- and 25-wk-old NOD.BDC mice. As shown in Fig. 6, young NOD.BDC thymus contained very
few CD8 single-positive T cells and a majority of CD4 single-positive T
cells were of the clonotype-high phenotype (8% idiotype-low
population). In contrast, old NOD.BDC thymus contained a significant
number of CD8 single-positive populations and a significant number of
CD4 single-positive cells with the clonotype-low phenotype (35%).
These results demonstrate an age-dependent change in the NOD.BDC
thymus. Both CD8-positive T cells that are of the clonotype-low
phenotype and clonotype-low CD4-positive single-positive T cells were
generated late in life and changed in the thymic T cell populations
coincident with the appearance of the clonotype-low T cells in the
peripheral lymphoid organs.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In this study, we demonstrated that, in NOD.BDC mice, CD4 T cells
expressing a high level of clonotype determinant are diabetogenic but
those expressing a low level of clonotype determinant are inhibitory.
The results of our transfer experiments are the most direct
demonstration of the function of these T cells. It should be noted that
CD4 T cells from normal prediabetic NOD mice are also shown to inhibit
diabetes transfer by spleen cells from diabetic mice (22).
We confirmed this result (A. Suri, unpublished data), but
clonotype-intermediate CD4 T cells used in this study were
significantly more effective for the inhibition of diabetes transfer
than the CD4 T cells from normal prediabetic NOD mice. In fact, 5
x 105 CD4 T cells from prediabetic NOD mice
failed to exhibit any inhibitory functions in this study (Table II
).
Diabetes can be induced in young NOD.BDC mice with a single injection of CY as shown previously by Andre-Schmutz et al. (19). However, old NOD.BDC mice were totally resistant to the same treatment. The appearance of clonotype-intermediate CD4 T cells coincides with the resistance to CY-induced diabetes. Furthermore, there were significant numbers of clonotype-low CD4 T cells in the NOD.BDC mice that remained diabetes free after CY treatment. Thus, our results with NOD.BDC mice do not support the original speculation that CY induces diabetes in NOD mice by eliminating suppressor/regulatory T cells (10). However, our results are in agreement with recent demonstration that CY injection activates diabetogenic BDC TCR-positive T cells via nonspecific activation of the inflammatory process (19). These findings need to be confirmed in normal NOD mice for the role of CY in the induction of diabetes.
Our results still do not explain why NOD.BDC mice failed to develop diabetes, since young mice have very few cells with regulatory T cell phenotypes. Analysis of the cells infiltrating the pancreas of NOD.BDC mice revealed that, even at the early stage of insulitis, both CD4 and CD8 T cells and B cells are present, similar to the previous report in normal NOD mice (2). Although we could not determine whether CD4 T cells infiltrating into islets are of the clonotype-high phenotype or not, it is possible that all T cells expressing islet Ag-specific TCR regardless of their functions can be recruited into the islet in this mouse line. Under such conditions, the number of regulatory T cell in the islets may be significantly higher than that in normal NOD mice and these T cells may functionally dominate to suppress diabetogenic processes. Thus, the insulitis seen in this mouse may represent a protective process rather than a prediabetic process. This would partially explain the presence of extensive cellular infiltrate into islets without diabetes development in NOD.BDC mice. It is also possible that extensive cellular infiltrate without diabetes in the mice treated with CFA (9) may also represent a similar regulatory T cell-dominant state. Studies of cellular migration into the islet for both diabetogenic and regulatory T cells and their interaction in vivo are necessary to fully understand the inhibition of the diabetic process in the NOD.BDC mouse model as well as in normal mice made resistant to diabetes by external manipulations.
Both CD4 and CD8 T cells with low clonotype expression develop only
late in life in NOD.BDC mice. Since these T cells are stained with
anti-V4 Ab with equal intensity as the
clonotype-high CD4 T cell population, it is likely that these T cells
express two TCR -chains (23), transgenic and an
endogenous TCR -chains paired with the transgenic TCR -chain. We
do not know what regulates this age-dependent generation of T cells
expressing two TCR on the surface. However, this delayed development of
T cells with regulatory function is reminiscent of that found
in normal mice. Thymectomy of 3-day-old mice eliminates
CD4+CD25+ regulatory T
cells without inhibiting the development of self-Ag-specific autoimmune
T cells (24, 25). These results indicate that both
CD4+CD25+ regulatory T
cells and regulatory T cells in BDC.NOD mice are generated in the
thymus. At present, we do not know what change in the thymus is
responsible for the generation of T cells with regulatory functions.
Thymic epithelial cells play an important role in the selection of
immature thymocytes (26). It is possible that certain
changes in the thymic epithelial cells may allow T cells expressing
both transgenic and endogenous TCR -chains paired with the
transgenic TCR -chain to mature into either CD4 or CD8
single-positive T cells. However, this does not explain how these
clonotype-low CD4 T cells acquire regulatory function. Further study of
the relationship between age-dependent change in the thymic environment
and the generation of T cells with unique surface phenotype and
regulatory function is needed to understand the regulation of
autoimmune diabetes as well as other organ-specific autoimmunity.
The exact relationship between
CD4+CD25+ regulatory T
cells and regulatory T cells expressing low idiotypic determinant in
NOD BDC mice is difficult to study. Studies of the expression of CD25
(Fig. 5) as well as a recently identified regulatory T cell marker,
2 integrin (27, 28), in the CD4 T
cells from the NOD.BDC mice showed no clear relationship between the
expression of these markers and the expression of clonotype. Recent
demonstration that some of the regulatory T cells also lack the CD25
marker (28) suggest that there may be no strict marker
besides their functions for the regulatory T cells. Analysis of the
clonotype-intermediate CD4 T cells with regulatory function identified
in this study for their thymic selection, acquisition of regulatory
functions, and change in the surface phenotype may provide useful
information to clarify the issues concerning this interesting cell
type.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Osami Kanagawa, Department of Pathology and Immunology, Washington University School of Medicine, Box 8118, 660 South Euclid Avenue, St. Louis, MO 63110. E-mail address: kanagawa{at}pathology.wustl.edu
3 Abbreviations used in this paper: IDDM, insulin-dependent diabetes mellitus; NOD, nonobese diabetic; CY, cyclophosphamide.
Received for publication January 8, 2002. Accepted for publication April 15, 2002.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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cell-reactive T cells is not restricted in non-obese diabetic mice. J. Exp. Med. 173:1091.-cell antigens to CD4+ and CD8+ T cells of non-obese diabetic mice. J. Immunol. 151:1723.[Abstract]
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cell apoptosis in T cell-mediated autoimmune diabetes. Proc. Natl. Acad. Sci. USA 94:213.-chain mutant. J. Immunol. 161:4489. genes but uses one heterodimer for allorecognition and self MHC-restricted antigen recognition. Cell 55:49.[Medline]
2 integrin, very late antigen-2). J. Immunol. 167:1141.This article has been cited by other articles:
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S.-K. Kim, K. V. Tarbell, M. Sanna, M. Vadeboncoeur, T. Warganich, M. Lee, M. Davis, and H. O. McDevitt Prevention of type I diabetes transfer by glutamic acid decarboxylase 65 peptide 206-220-specific T cells PNAS, September 28, 2004; 101(39): 14204 - 14209. [Abstract] [Full Text] [PDF]
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Q. Tang, K. J. Henriksen, M. Bi, E. B. Finger, G. Szot, J. Ye, E. L. Masteller, H. McDevitt, M. Bonyhadi, and J. A. Bluestone In Vitro-expanded Antigen-specific Regulatory T Cells Suppress Autoimmune Diabetes J. Exp. Med., June 7, 2004; 199(11): 1455 - 1465. [Abstract] [Full Text] [PDF]
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A. E. Herman, G. J. Freeman, D. Mathis, and C. Benoist CD4+CD25+ T Regulatory Cells Dependent on ICOS Promote Regulation of Effector Cells in the Prediabetic Lesion J. Exp. Med., June 7, 2004; 199(11): 1479 - 1489. [Abstract] [Full Text] [PDF]
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N. Martin-Orozco, Z. Chen, L. Poirot, E. Hyatt, A. Chen, O. Kanagawa, A. Sharpe, D. Mathis, and C. Benoist Paradoxical Dampening of Anti-Islet Self-Reactivity but Promotion of Diabetes by OX40 Ligand J. Immunol., December 15, 2003; 171(12): 6954 - 6960. [Abstract] [Full Text] [PDF]
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E. E. Hamilton-Williams, S. E. Palmer, B. Charlton, and R. M. Slattery Beta cell MHC class I is a late requirement for diabetes PNAS, May 27, 2003; 100(11): 6688 - 6693. [Abstract] [Full Text] [PDF]
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N. J. Hill, K. Van Gunst, and N. Sarvetnick Th1 and Th2 Pancreatic Inflammation Differentially Affects Homing of Islet-Reactive CD4 Cells in Nonobese Diabetic Mice J. Immunol., February 15, 2003; 170(4): 1649 - 1658. [Abstract] [Full Text] [PDF]
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) and young (8 wk old, •) mice
were stimulated with an indicated number of irradiated (2000 rad)
B10.Br-derived pancreatic 
),
idiotype-intermediate (
), and a mixture of both (
) CD4 T cells
(4 x 104/culture) were stimulated with irradiated 
