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Harrison Department of Surgical Research, University of Pennsylvania School of Medicine, Philadelphia, PA 19104
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResults and DiscussionReferences |
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cells has occurred.
Furthermore, µMT-/- NOD mice are shown to harbor a
latent repertoire of diabetogenic T cells, as evidenced by their
susceptibility to cyclophosphamide-induced diabetes. The quiescence of
this pool of islet-reactive T cells may be a consequence of impaired
activation of T lymphocytes in B cell-deficient NOD mice. In this
regard, in vitro anti-CD3-mediated stimulation demonstrates
impaired activation of lymph node CD4 T cells in µMT-/-
NOD mice as compared with that of wild-type counterparts, a deficiency
that is correlated with an exaggerated CD4 T cell:APC ratio in lymph
nodes of µMT-/- NOD mice. This feature points to an
insufficient availability of APC costimulation on a per T cell basis,
resulting in impaired CD4 T cell activation in lymph nodes of
µMT-/- NOD mice. In accordance with these findings, an
islet-reactive CD4 T cell clonotype undergoes suboptimal activation in
pancreatic lymph nodes of µMT-/- NOD recipients.
Overall, the present study indicates that B cells in the pancreatic
lymph node microenvironment are critical in overcoming a checkpoint
involving the provision of optimal costimulation to islet-reactive NOD
CD4 T cells. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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cells
(2, 3). Numerous studies have been focused on
identification of the Ag(s) and APC population(s) responsible for the
activation of islet-reactive T lymphocytes. Importantly, it has become
clear that B cell-deficient NOD mice are protected from spontaneous
diabetes, suggesting that B lymphocytes are critical APCs in NOD
diabetogenesis (4, 5, 6, 7). By virtue of their Ag receptor
specificity, B lymphocytes efficiently process and present a high
density of antigenic epitopes, making them a likely candidate APC
population for presentation of islet autoantigens in vivo
(8, 9, 10, 11, 12, 13, 14, 15). In this regard, we and others have demonstrated a
requirement for B lymphocytes as critical APCs in the development of
fulminant insulitis and spontaneous diabetes in NOD mice
(16, 17, 18). Given the importance of cognate T/B interaction to the pathogenesis of diabetes, we reasoned that diabetes resistance in B cell-deficient (µMT-/-) NOD mice may be the result of inefficient activation of diabetogenic T cells. The present study demonstrates impaired activation of islet-reactive CD4 T cells in the pancreatic lymph node of µMT-/- NOD mice, suggesting the critical role of B lymphocytes in the lymph node microenvironment for the effective provision of costimulatory signals to diabetogenic T cells.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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NOD/LtJ, NOD/scid, NOD.NONThy-1.1, BALB/c, C57BL/6
(B6), and µMT-/- B6 mice were purchased from
The Jackson Laboratory (Bar Harbor, ME). BDC2.5 NOD and TCR
C
-/- NOD mice were generously provided by C.
Benoist and D. Mathis (Joslin Diabetes Center, Harvard University,
Boston, MA). µMT-/- NOD mice (N10 backcross)
were generated as previously described (18). All mice were
housed under specific pathogen-free barrier conditions at the
University of Pennsylvania; mice on the NOD background were monitored
weekly for the development of spontaneous diabetes. There has not been
a single µMT-/- NOD mouse that has become
diabetic spontaneously in our colony, with some mice being monitored to
an age of 50 wk. Blood glucose levels were measured with Accu-Chek
Advantage test strips (Boehringer Mannheim, Indianapolis,
IN); diabetes was defined as readings of >250 mg/dl on 2
consecutive days.
Histology
From each pancreas, 5–10 pairs of serial sections stained with
H&E and aldehyde fuchsin (which stains islet cells dark
blue) were cut at 50-µm intervals (to avoid multiple assessments of
the same islet), and examined for the presence of mononuclear cell
infiltration. A total of 40–100 islets per animal was graded (in a
blinded fashion) as follows: 0 = no inflammation (islet is
completely free of mononuclear cell infiltration); 1 =
peri-insulitic (poles of mononuclear cell infiltration directly
adjacent to or involving <50% of the islet area); 2 = insulitic
(>50% of the islet area is disrupted, or completely surrounded, by
mononuclear cell infiltrate).
Cyclophosphamide treatment
Mice were injected i.p. with 200 mg/kg cyclophosphamide (CyP; Cytoxan, Mead Johnson, Princeton, NJ) dissolved in PBS. Two weeks following the initial treatment, mice remaining nondiabetic were given a second injection and followed for additional 4 wk. Mice were monitored every 3 days for the development of diabetes, as described above.
Adoptive transfer of diabetes
A total of 20–25 million cells harvested and pooled from spleen
and lymph nodes of donor µMT-/- NOD mice was
injected into the tail vein of recipient TCR
C-/- NOD mice. Diabetes was monitored by
weekly blood glucose measurements for 25 wk after adoptive
transfer.
CFSE labeling of lymphocytes
Lymphocytes were labeled with CFSE (Molecular Probes, Eugene, OR), as previously described (19). Briefly, splenocytes or lymph node cells were resuspended at a concentration of 10 x 106 cells/ml in serum-free IMDM (Life Technologies/BRL, Gaithersburg, MD) at 37°C. An equal volume of a 1/350 dilution of the CFSE stock (5 mM in DMSO) in 37°C serum-free IMDM was then added to the cell preparation, which was subsequently incubated for 5 min at 37°C. CFSE labeling was quenched by adding an equal volume of heat-inactivated FCS (HI-FCS), whereupon cells were washed twice and resuspended in IMDM containing 10% HI-FCS.
In vitro T cell stimulations
CFSE-labeled splenocytes or pooled lymph node cells (inguinal, axillary, and cervical) were plated in 24-well plates at a density of 1 x 106 total cells in 1 ml media containing 10% HI-FCS with the designated amount of anti-CD3 (145-2C11) and 2 µg/ml anti-CD28 (37.51) mAbs. Maximal division occurred upon activation with a dose of 2 µg/ml anti-CD3 mAb. All cells were incubated for 65–70 h at 37°C in 7% CO2. After incubation, the cultured cells were harvested and stained with allophycocyanin-conjugated anti-CD4 (RM4-5; BD PharMingen, Torrey Pines, CA) to allow the identification of CFSE-labeled CD4 T cells using flow cytometry. Ten thousand CD4+ events were collected within a live cell gate, which included blasting cells, as determined by forward and side scatter.
Flow cytometry
A total of 1 x 106 cells was surface
stained in 96-well plates with different mAbs: 53-6.7 FITC
(anti-CD8a), M1/70 PE (anti-CD11b), RA3-6B2 biotin
(anti-CD45R/B220), RM4-5 allophycocyanin (anti-CD4), 10-3.6
(anti-I-Ag7), AF6-120.1 PE
(anti-I-Ab), KT4 biotin (anti-V4 TCR),
OX-7 PE (anti-CD90.1/Thy-1.1), 30-H12 biotin
(anti-CD90.2/Thy-1.2) (BD PharMingen). Biotin-conjugated mAbs were
subsequently stained with streptavidin-RED670 (Life Technologies). All
samples were analyzed on a FACSCalibur flow cytometer (Becton
Dickinson, Mountain View, CA) using CellQuest software. Subsequent
analysis was performed using FlowJo software.
Analysis of cell division
Gates for each division peak were set utilizing live gated
cells; thereafter, live and dead cells were included in analysis, as
previously described (20, 21), based on the property of
CFSE-labeled cells to lose half of their fluorescence intensity with
each round of division. Briefly, cell counts for each division peak,
undivided cells (peak 0), and total gated CD4+
cells were determined using FlowJo (http://www.flowjo.com) and exported
into Microsoft Excel (http://www.microsoft.com) for analysis. The
number of precursor cells that gave rise to daughter cells in each peak
was determined by multiplying the normalized number of cells in a given
peak, "N," by the factor 1/2n, in which
"n" is the division peak number. The total number of mitotic events
that gave rise to the resulting division profile could then be closely
approximated using the formula:
(N(2n -
1)/2n). Precursor frequency calculations were
performed to determine the percentage of cells from the original
undivided pool that were recruited into the dividing pool (total number
of dividing precursors/total number of precursor cells). Dose-response
analysis was performed by setting as 100% mitosis, for each individual
animal, the number of mitotic events achieved with the maximal dose of
anti-CD3.
Selective depletion of lymphocyte populations
Specific depletion of lymphocyte populations was accomplished by negative selection of splenocytes or lymph node cells via MACS. Enriched populations of T cells were prepared by depleting with anti-B220 biotin (RA3-6B2) and anti-CD11b biotin (M1/70) mAbs, followed by streptavidin-conjugated MACS beads, which were then passed through columns using the VarioMACS system (Miltenyi Biotec, Sunnyvale, CA). All depletions yielded >95% efficiency in negative selection of the targeted population, as determined by flow cytometry.
In vivo tracking of islet-reactive CD4 T cell division
Splenocytes and lymph node cells were isolated from NOD (or
Thy-1.1 NOD congenic) BDC2.5 TCR transgenic mice and enriched for T
cells before CFSE labeling, as described above. A total of 10–20
x 106 of these CFSE-labeled T cells was injected
by tail vein into wild-type (µMT+/+ or
µMT+/-) and µMT-/-
NOD mice. For BDC2.5 T cell transfers, optimal activation has been
shown to occur at about 85–90 h (22), and so recipient
cells were harvested at this time point from spleen, nonpancreatic
lymph nodes (pooled inguinal, axillary, and cervical), and pancreatic
lymph nodes (typically three lymph nodes draining the pancreas were
harvested using a dissecting microscope). Single cell suspensions were
prepared and stained with anti-Thy-1.1 PE (OX-7) and/or
anti-TCR V4-bio (the BDC2.5 transgene utilizes V4 TCR) and
anti-CD4 APC (RM4-5) to allow for the identification of the
transferred CD4 T cells using flow cytometry, as described above. A
total of 5,000–10,000
CFSEbright/CD4+/V4+
or CD4+/Thy-1.1+ events was
collected within a live lymphoid gate including blasting cells, as
determined by forward and side scatter. Division history was
subsequently analyzed, as described above. The normalized number of
mitoses occurring in wild-type recipients was set as 100% mitotic
activity for each experiment. Extent of division achieved by
transferred cells in experimental animals was then calculated as a
percentage of wild-type mitotic activity and averaged for five separate
experiments.
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Results and Discussion |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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It is not clear whether protection of
µMT-/- NOD mice from spontaneous diabetes is
a result of arrested initial targeting of islet cells or impaired
progression of the anti-islet T cell response. Thus, to determine
whether islet cell targeting occurs in the absence of B
lymphocytes, we undertook a systematic histological analysis of
pancreata from µMT-/- NOD mice. We examined
pancreata from a large cohort of µMT-/- NOD
mice that had remained free from diabetes to a late age
(n = 19, 30–50 wk old). In this cohort of animals, a
total of 1492 individual islets was scored for the presence of islet
inflammation. While 73% of these islets in aggregate were free of
mononuclear cell infiltration, pancreata from all mice examined
exhibited some degree of insulitis (Table I
). There was wide variation in the
percentage of islets affected among individual animals (mean =
25.8%; range = 2.8–66.7%). We next analyzed 396 islets from a
cohort of younger µMT-/- NOD mice
(n = 6, 10–12 wk old). In aggregate, 94% of these
islets were free of infiltration. In contrast to the older mice, some
younger mice were completely free of insulitis (mean = 6.1%;
range = 0–10.8%). Overall, islet inflammation was significantly
more prevalent in older than in younger
µMT-/- NOD mice (p
value = 0.01, Table I). The typical lesion in
µMT-/- NOD mice consisted of a pole of
mononuclear cells at the periphery of the islet (Fig. 1, A and B); only
rarely (4.1% of islets in older mice) was the islet inflammation
extensive enough to disrupt islet architecture (Fig. 1, C
and D). As expected, the majority of islets in all control B
cell-sufficient littermates (72% in older mice; 61% in younger mice)
exhibited insulitis (Fig. 1, E and F). Although
the islet inflammation seen in B cell-deficient NOD mice was of a
benign nature, its existence indicated that the cells in these mice
were targeted by the immune system. However, it appears that in the
absence of B lymphocytes, the anti-islet T cell response is not
sufficiently activated to mediate diabetes. The nondestructive
targeting of islets attests to a suboptimal capacity of non-B cell APCs
(macrophages and dendritic cells) to activate islet-reactive T cells in
B cell-deficient NOD mice.
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Since islet cells in µMT-/- NOD mice
demonstrated evidence of mild insulitis, we sought to determine whether
a latent potential for progression to diabetes exists in these mice.
CyP has been used to accelerate the onset of diabetes in NOD mice and
is considered a reliable agent to convert a nonprogressive insulitis to
a destructive state (23, 24, 25, 26, 27). Therefore, cohorts of
µMT-/- and littermate control
(µMT+/+ or µMT+/-) NOD
mice that had reached an age of 30–50 wk without becoming diabetic
were treated with CyP and followed for the development of diabetes. We
also treated a cohort of younger (10- to 20-wk-old)
µMT-/- (and control
µMT+/-) NOD mice to determine the functional
significance of the mild islet inflammation seen in these mice. As
expected, a majority of B cell-sufficient control NOD mice became
diabetic within 4 wk of CyP treatment. Intriguingly, CyP also induced
diabetes in a proportion of older µMT-/- NOD
mice (Table II). This finding
demonstrates that B cell-deficient NOD mice indeed retain a latent
potential for progression to diabetes. However, in line with their
significantly milder degree of islet infiltration, younger
µMT-/- NOD mice were completely resistant to
CyP-induced diabetes. Of note, the proportion of
µMT-/- NOD mice susceptible to
CyP-induced diabetes (2/27) was comparable with the proportion of
µMT-/- NOD mice having >50% of their islets
inflamed (3/25; Table I
). The susceptibility of
µMT-/- NOD mice to CyP-induced diabetes
suggested the existence of islet-reactive specificities in the
peripheral immune repertoire of these mice. We confirmed that such
islet-reactive specificities exist by performing adoptive transfer of
µMT-/- NOD lymphocytes into T cell-deficient
TCRC-/- NOD mice; two of three recipients
subsequently became diabetic within 15 wk. These findings are in
agreement with a recent study demonstrating the development of diabetes
in NOD/scid mice after similar transfers of
µMT-/- NOD T cells were performed
(28).
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The existence of islet inflammation in the pancreata of
µMT-/- NOD mice indicated early targeting of
cells by islet-reactive T cells. However, this population had
failed to become sufficiently activated to cause spontaneous diabetes.
A logical explanation for this failure is that NOD non-B cell APCs
might be impaired in their ability to support the efficient activation
of islet-reactive T lymphocytes. We have previously shown that in
response to TCR/CD3-mediated stimulation, NOD CD4 T cells exhibit an
impaired division capacity compared with nonautoimmune strain mice.
Specifically, when CFSE-labeled NOD splenocytes were stimulated by
anti-CD3/CD28 mAbs, CD4 T cells exhibited division arrest and
failed to generate daughter cells in as advanced division peaks as
those achieved by their nonautoimmune counterparts (20).
Interestingly, when splenocytes were depleted of B cells in vitro, CD4
T cells failed to initiate division, even upon maximal stimulation by
anti-CD3/CD28. This finding indicated that the observed CD4 T cell
activation defect resided in the inability of NOD non-B cell APCs to
provide optimal costimulatory signals. We therefore sought to determine
whether the protection from diabetes seen in
µMT-/- mice resulted from disruption of CD4 T
cell division as a consequence of the reduced costimulatory capacity of
NOD non-B cell APCs. Surprisingly, when CFSE-labeled
µMT-/- NOD splenocytes were cultured with a
maximally stimulatory dose of anti-CD3/CD28, CD4 T cells exhibited
a division profile that was similar to wild-type NOD mice (Fig. 2A). Specifically, the
division profile of both wild-type and µMT-/-
NOD splenic CD4 T cells revealed a majority of daughter cells in
divisions 1–4 and a comparable dose responsiveness to
anti-CD3/CD28 (Fig. 2B). Similarly, a lack of B cells in
the spleen of nonautoimmune B6 mice appeared to have a minimal impact
on CD4 T cell mitotic activity, with µMT-/-
B6 splenocytes demonstrating a dose responsiveness similar to wild-type
counterpart B6 mice (Fig. 2B).
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). Using these
maximally stimulated division profiles, the frequency of CD4 T cells in
the starting pool that were recruited to divide was calculated. This
analysis revealed that, compared with wild-type counterparts, very few
lymph node CD4 T cells from µMT-/- NOD mice
entered the dividing pool following 70 h of maximal stimulation by
anti-CD3/CD28 (5.9 ± 1% for µMT-/-
vs 50.5 ± 6% for wild type). Importantly, this degree of
impairment was not observed in lymph node CD4 T cells from
µMT-/- B6 mice (Fig. 3), indicating
sufficient availability of non-B cell APC-mediated costimulation in
these nonautoimmune mice. It is well established that T cell
proliferation in response to soluble anti-CD3/CD28 mAb stimulation
is an APC-dependent process, and that T cell:APC ratio is an important
parameter influencing the degree of proliferation. Therefore, the
suboptimal proliferative response of CD4 T cells from lymph nodes of
µMT-/- NOD mice may be attributable to a
perturbation in the ratio of CD4 T cell:non-B cell APC. Importantly,
compared with lymph nodes from wild-type NOD mice, the
µMT-/- NOD lymph nodes contained a markedly
greater CD4:APC ratio (1.4 for wild-type vs 51.9 for
µMT-/-; Table III). The skewed ratio of CD4:APC in
µMT-/- NOD lymph nodes suggests that the
impaired CD4 T cell activation profile may be a reflection of a reduced
availability of APC costimulatory input on a per CD4 T cell basis.
Interestingly, our data demonstrating a pronounced alteration in
CD4:APC ratio may help to explain previously reported defects in the
ability of CD4 T cells to support immune responses in B cell-deficient
mice (30). By extension, an inability of islet-reactive
CD4 T cells to become optimally activated in the pancreatic lymph nodes
of µMT-/- NOD mice may result in their
protection from spontaneous diabetes. In the next section, we directly
assess this possibility in vivo.
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The BDC2.5 TCR transgene encodes an islet-specific CD4 T cell
clonotype that has been shown to be preferentially activated in
pancreatic lymph nodes (31). Following transfer to NOD
mice, CFSE-labeled BDC2.5 CD4 T cells preferentially underwent several
rounds of division upon homing to pancreatic lymph nodes, but not in
other secondary lymphoid organs (22). We utilized this
unique strategy to track the division history of adoptively transferred
CFSE-labeled BDC2.5 T cells in both µMT-/-
and wild-type NOD recipients. By day 4 following adoptive transfer,
BDC2.5 CD4 T cells underwent up to eight rounds of division in the
pancreatic lymph nodes of control B cell-sufficient NOD recipient mice
(Fig. 4A). In the experimental
group, we analyzed the division profile of adoptively transferred
CFSE-labeled BDC2.5 T cells in pancreatic lymph nodes of
µMT-/- NOD recipients. We standardized the
extent of division in µMT-/- NOD mice by
using the level of mitotic activity in wild-type mice in each
experiment as the maximal level of division. We were therefore able to
determine the degree to which the division potential of islet-reactive
CD4 T cells was attained in the absence of B cells. This analysis
revealed that, on the average, BDC2.5 CD4 T cells transferred into
µMT-/- NOD recipients achieved approximately
one-half (49.3%; n = 9; p = 0.007) of
the maximal division capacity seen in B cell-sufficient controls (Fig. 4A). Importantly, transferred islet Ag-specific BDC2.5 cells
failed to undergo division in either spleen or nonpancreatic lymph
nodes (Fig. 4B). These findings directly demonstrate a
significant impairment in the ability of B cell-deficient NOD
pancreatic lymph nodes to support optimal activation of a bona fide
islet-reactive CD4 T cell clonotype.
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cell destruction.
Overall, the above data demonstrate an impairment of CD4 T cell
activation in lymph nodes of B cell-deficient NOD mice that may result
from suboptimal delivery of costimulation from the non-B cell APC
compartment of NOD mice. The present study demonstrates that although B
cell-deficient NOD mice harbor anti-islet T cells, they fail in
becoming activated to a level required for islet cell destruction.
Indeed, we directly demonstrate deficient activation of islet-reactive
CD4 T cells in the absence of B lymphocytes. Based on these results, we
suggest that the indispensable role of B cells in NOD diabetogenesis is
their necessity for optimal activation of an islet-specific T cell
response in the pancreatic lymph node microenvironment.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Ali Naji, Department of Surgery, 4 Silverstein Pavilion, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104. E-mail address: alinaji{at}uphs.upenn.edu
3 Abbreviations used in this paper: NOD, nonobese diabetic; CyP, cyclophosphamide; HI-FCS, heat-inactivated FCS.
Received for publication June 8, 2001. Accepted for publication August 2, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
), B6 wild type (
), and B6 µMT-/- (
) in three
separate experiments.
