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,
*
The Jackson Laboratory, Bar Harbor, ME 04609; and Departments of
Microbiology and Immunology and
Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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ß Tg) continued
to develop IDDM at a greatly accelerated rate when residual CD4 helper
T cells were eliminated by introduction of the scid
mutation or a functionally inactivated CD4 allele. In a
previously described stock of NOD mice expressing TCR transgenes
derived from another MHC class I-restricted ß cell autoreactive T
cell clone, IDDM development was retarded by elimination of residual
CD4 T cells. Hence, there is variability in the helper dependence of
CD8 T cells contributing to the development of autoimmune IDDM. The AI4
clonotype represents the first CD8 T cell with a demonstrated ability
to progress from a naive to functionally activated state and rapidly
mediate autoimmune IDDM development in the complete absence of CD4 T
cell helper functions. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Given their indispensable diabetogenic role, it is important to identify the mechanisms that enable MHC class I-restricted ß cell-autoreactive CD8 T cells to develop and exert their pathogenic functions. The goal of the present study was to determine whether MHC class I-restricted ß cell-autoreactive T cell responses essential to IDDM development in NOD mice could still be generated in the absence of helper functions provided by MHC class II-restricted T cells. This issue was addressed through the use of a newly developed NOD mouse stock that transgenically expresses the TCR from a MHC class I-restricted CD8 clone that contributes to the earliest initiative phases of autoimmune ß cell destruction.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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NOD/Lt mice are maintained at The Jackson Laboratory by
brother-sister mating. Currently, IDDM develops in 90% of female and
63% of male NOD/Lt mice by 1 year of age. Stocks of NOD mice
transgenically expressing the rearranged TCR - and/or ß-chain
genes from the previously described (17)
Kd-restricted ß cell-autoreactive CD8 T cell
clone AI4 were produced as follows. TCR and -ß shuttle vectors
(18, 19) were kindly provided by Dr. Mark Davis (Stanford
University, Stanford, CA). The VJ segment of the AI4 TCR -chain cDNA
(V8) was amplified by PCR using primers containing appropriate
intronic sequences, splice acceptor/donor sites, and restriction sites
for cloning into the XhoI/NotI sites of the
TCR shuttle vector. The VDJ segment of the TCR ß-chain cDNA
(Vß2) was similarly amplified and cloned into the
ClaI/NotI sites of the TCRß shuttle vector.
Prokaryotic sequences were removed by digestion with
ClaI/SalI (TCR) or
PvuI/SalI (TCRß). These transgene constructs
were separately injected directly into naturally ovulated NOD/Lt
zygotes by the Microinjection Service of The Jackson Laboratory and
implanted without prior culture into pseudopregnant (B6 x
SJL)F1 females. Offspring carrying the AI4 TCR
-chain transgene (designated NOD.AI4 Tg) were identified by PCR
using the primer set 5'-CTCCGTGACCCAGACAGAAGG-3' and
5'-TTCCAGTGTTAGCACCAGCCG-3'. Carriers of the AI4 TCR ß-chain
transgene (designated NOD.AI4ß Tg) were identified by PCR using the
primer set 5'-GCTGGAGCAAAACCCAAGGTG-3' and
5'-GTATTTCCTAGCCCCCTGTGTG-3'. TCR transgene expression was
confirmed by flow cytometry as described below. NOD mice carrying both
the AI4 TCR - and ß-chain transgenes (designated NOD.AI4ß Tg
mice) were then produced through intercrossing. Previously described
IDDM-resistant strains of NOD-scid (official designation
NOD-Prkdcscid) and
NOD.ß2mnull mice (official designation
NOD.B2mtm1Unc) are each maintained at the N11
backcross generation (14, 20). These two strains served as
progenitors for two new stocks respectively designated
NOD-scid.AI4ß Tg and
NOD-ß2mnull.AI4ß Tg. NOD-scid
homozygotes were outcrossed to mice carrying the AI4 TCR transgenes.
The subsequent F1 progeny were backcrossed to
NOD-scid to produce offspring homozygous for scid
and heterozygous for the AI4 TCR transgene constructs. A similar method
was used to generate AI4 TCR Tg NOD mice homozygous for the
ß2mnull mutation. An N8 backcross stock
of NOD mice homozygous for a CD4null
allele (Ref. 21 ; official designation
Cd4tm1Knw)), as well as genetic linkage
markers delineating all known diabetes susceptibility (Idd)
loci of NOD origin, was produced by our previously described "speed
congenic" approach (22). NOD mice homozygous for the
CD4null allele and carrying the AI4 TCR
transgenes were produced as described above. All mice are housed under
specific pathogen-free conditions and allowed free access to food
(Agway Diet NIH 31A; Agway, South Henly, MO) and acidified drinking
water. NOD-scid stocks received
trimethoprim-sulfamethoxazole supplement (Sulfatrim; Barre-National,
Baltimore, MD) 3 days per wk.
Assessment of diabetes development
Diabetes development in the indicated mice was defined by
glycosuric values of 
3 as assessed with Ames Diastix (kindly supplied
by Miles Diagnostics, Elkhart, IN).
T cell subset enumerations
Peripheral blood leukocytes (PBL) from the indicated mice were
assessed for CD4 and CD8 T cell levels and the proportion of these that
express Tg AI4 TCR elements by multicolor flow cytometric techniques
(FACScan; Becton Dickinson, San Jose CA) using the CellQuest 3.0 data
reduction system. Total T cells were detected with the
TCRß-specific mAb H57-597 conjugated to a green fluorescent FITC
tag. Total T cells were then further characterized for CD4 expression
using the mAb GK1.5 conjugated to the red fluorescent tag Cy3.18-OSu
(Cy3; Biological Detection Systems, Pittsburgh, PA) or for CD8
expression with the mAb 53-6.72 conjugated to PE whose red fluorescence
intensity can easily be distinguished from that of Cy3. A separate
aliquot of PBL from each mouse was assessed by two-color FACS analysis
for Tg AI4 - and/or ß-chain expression by respective use of PE- or
FITC-conjugated Abs specific for TCR V8 (B21.14) or Vß2 (B20.6)
elements.
Statistical analyses
Rates of IDDM development in the indicated experimental groups were assessed for statistically significant differences by Kaplan-Meier life table analysis using the Statview 4.5 computer software program (Abacus Concepts, Berkeley, CA).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We previously isolated from islets of standard 5–6-wk-old NOD
female mice, a series of Kd-restricted ß
cell-autoreactive CD8 T cell clones contributing to the earliest
initiative phases of IDDM development (17). Subsequently,
rearranged TCR - and ß-chain genes were isolated from one of these
T cell clones (AI4) and individually introduced as transgenes directly
into NOD mice (designated NOD.AI4 Tg or NOD.AI4ß Tg mice). NOD
mice carrying both the AI4 TCR - and ß-chain transgenes
(designated NOD.AI4ß Tg mice) were then selected from intercross
progeny. The female incidence of IDDM in these three TCR Tg stocks
was then compared with that of transgene negative segregants.
Most significantly, when compared with nontransgenic controls,
NOD.AI4ß Tg mice exhibited a greatly accelerated rate of IDDM
development (p < 0.0001, Kaplan-Meier life
table analysis), with disease first observed as early as 3 wk of age
(Fig. 1
). The NOD.AI4 Tg
line developed IDDM at a slightly faster, but not significantly
different rate than nontransgenic controls. Interestingly, expression
of the AI4ß Tg alone exerted a significant protective effect
(p = 0.0045) in which both the frequency and
rate of IDDM development were inhibited. One possible explanation for
these latter two results is that the antigenic specificity of
diabetogenic CD8 T cells in NOD mice may be primarily imparted through
expression of particular TCR -chain rather than ß-chain gene
rearrangements. Support for this possibility is provided by our
previous finding that the CD8 T cells initiating IDDM development in
NOD mice utilize a relatively restricted set of TCR
-chains coupled with a diverse array of TCR ß-chains
(17). However, another mechanism could also account for
the relative IDDM resistance of NOD mice expressing the AI4ß Tg
alone. A greater extent of allelic exclusion is usually observed at the
TCR ß-chain than -chain locus (23). As a result, the
total T cell repertoire could be less diverse in NOD mice solely
carrying the AI4ß than AI4 Tg construct, which in turn could limit
IDDM development.
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ß Tg can also be expressed in
the CD4 lineage
Due to the process of allelic exclusion, mice carrying rearranged
TCR - and ß-chain transgenes predominantly produce the T cell
clonotype encoded by the transgenes (24). However, allelic
exclusion, particularly within the TCR -chain is an incomplete
process (reviewed in Ref. 23). For this reason, TCR Tg
mice usually continue to produce some fraction of T cells that express
endogenously derived TCR molecules. Hence, we reasoned that some T
cells which fail to express AI4 TCR elements might be exerting IDDM
promotive or inhibitory effects in our NOD TCR Tg stocks. Thus, we
assessed what types and proportions of T cells in our NOD TCR
Tg stocks expressed AI4 TCR elements. In the NOD.AI4 Tg stock, T
cells expressing the single Tg TCR -chain comprised 
30% of the
total PBL population (Table I). PBL from
this stock consisted of 25% CD4 and 8% CD8 T cells. This
indicated that although 91% of the total T cells in NOD.AI4 Tg
mice express the Tg TCR -chain, a significant fraction of these
reside within the CD4 rather than the expected CD8 lineage. A similar
situation was observed in NOD.AI4ß Tg mice (Table I). In the
NOD.AI4ß Tg stock, 96% of the total T cells expressed the two
Tg TCR elements, but half of these still resided within the unexpected
CD4 lineage.
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ß Tg mice are
selected through coexpression of a second TCR
The data described above suggested the unexpected population of
CD4 T cells present in NOD.AI4ß Tg mice could contribute to their
accelerated rate of IDDM development. For this reason, we
evaluated the developmental basis of CD4 T cells in the
NOD.AI4ß Tg stock. There have been previous reports that
due to incomplete allelic exclusion, TCR Tg mice can develop T cells
that express a second endogenously derived TCR (25, 26, 27).
Thus, although they express the AI4 TCR, we reasoned the selection and
functional activities of CD4 T cells in NOD.AI4ß Tg mice could
actually be mediated through their coexpression of a second TCR.
Presence of the scid mutation blocks the productive
rearrangement of germline TCR gene segments (28). The
scid mutation has already been fixed on the inbred NOD
background (20). Thus, we were able to produce through a
single outcross-intercross cycle NOD.AI4ß Tg mice that were also
homozygous for the scid mutation. FACS analysis revealed a
complete absence of CD4 T cells in these NOD-scid AI4ß
Tg mice (representative profile in Fig. 2; data summarized in Table II). However, AI4 TCR transgene
expressing CD8 T cells remained present. Hence, the CD4 T cells present
in standard NOD.AI4ß Tg mice are not selected through the Tg TCR,
but rather a second endogenously derived TCR. To further address this
issue, we crossed the AI4ß Tg constructs onto the previously
described stock (14) of NOD mice that were made MHC class
I deficient by a functionally inactivated
ß2-microglobulin gene
(NOD.ß2mnull). Converse to the effect
induced by the scid mutation, ß2m-deficient
NOD.AI4ß Tg mice developed CD4, but not CD8 T cells expressing the
Tg AI4 TCR (representative profile in Fig. 2; data summarized in Table II). Since the AI4 TCR is restricted to the Kd
MHC class I gene product, the above finding also indicated that the CD4
T cells present in standard NOD.AI4ß Tg mice are actually selected
through a second endogenously derived TCR that is MHC class II
restricted.
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ß Tg mice, as well
as in those carrying the scid or
ß2mnull mutations, a small population of
CD4-CD8-
TCR+ cells could be detected (Fig. 2
). A
significant fraction of NK T cells have been reported to lack both CD4
and CD8 expression (29). NK T cell development is
dependent on expression of the class I-like molecule CD-1. However, the
CD4-CD8-
TCR+ cells present in NOD.AI4ß Tg mice are
unlikely to represent NK T cells since they are not eliminated in the
presence of the ß2mnull mutation which
blocks CD-1 expression. Instead, we consider it most likely that the
small population of
CD4-CD8-
TCR+ cells found in NOD.AI4ß Tg mice develop
as a consequence of the transgene-encoded TCR being expressed at an
earlier stage of T cell development than is normally the case for
endogenously derived TCR molecules. Indeed, a Tg TCR derived from
another MHC class I-restricted ß cell-autoreactive T cell clone clone
of NOD origin (NY8.3) has been shown to be expressed at an early
CD4-CD8- stage of T cell
development (30). CD8 T cells expressing the AI4 TCR can independently mediate IDDM development
Perhaps the most striking observation in these studies was
that compared with standard NOD mice, IDDM continued to develop at a
greatly accelerated rate in the NOD-scid AI4ß Tg
stock (p < 0.0001) (Fig. 3). Conversely, while possessing AI4
TCR-positive CD4 T cells,
NOD.ß2mnull.AI4ß Tg mice were
completely IDDM resistant (p = 0.0002 vs NOD
controls). Histological examination of pancreatic tissue revealed
extensive insulitis in NOD-scid AI4ß Tg mice, whereas
islets from NOD.ß2mnull.AI4ß Tg
mice were completely free of infiltrating leukocytes (data not shown).
These collective results indicated that MHC class I-restricted CD8 T
cells expressing the AI4 TCR can mediate IDDM development in NOD mice
in the complete absence of help provided by MHC class II-restricted CD4
T cells. However, as an additional test of this issue, we crossed the
AI4ß Tg constructs onto a stock of NOD mice carrying a
functionally inactivated CD4 gene
(CD4null). These
NOD.CD4null mice are normally completely
IDDM resistant (0/18 females diabetic by 30 wk of age). In contrast,
six of eight NOD.CD4null females that
expressed the AI4ß Tg constructs developed IDDM with a mean age of
onset of 7 wk. These results further support the conclusion that MHC
class I-restricted AI4 clonotypic T cells can independently mediate the
development of autoimmune IDDM in NOD mice.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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ß-chain elements from the MHC
class I-restricted ß cell-autoreactive T cell clone NY8.3
(30). However, the rate and frequency of IDDM development
in the NY8.3 TCR Tg stock was greatly reduced when the residual
nontransgenic CD4 T cells were eliminated by introduction of a
functionally inactivated Rag-2 allele. In contrast,
elimination of residual CD4 T cells by introduction of the
scid mutation did not impede the greatly accelerated rate of
IDDM development observed in the NOD.AI4ß Tg stock. Collectively,
these results indicate that the ß cell-autoreactive CD8 T cells which
are essential contributors to IDDM development in NOD mice vary in
their helper factor dependence. However, the most important finding in
the current study was that some MHC class I-restricted T cell
clonotypes, such as AI4, can efficiently mediate autoimmune IDDM
development in the complete absence of CD4 T cell helper
activities. Although essential to the process, CD8 T cells isolated from standard NOD mice cannot independently mediate IDDM development (13, 16, 17). This might be due to the fact that in standard NOD mice the frequency of CD8 T cell clonotypes such as AI4 that can independently mediate IDDM development is lower than in a TCR-transgenic situation. Thus, most of the CD8 T cell repertoire that contributes to IDDM development in standard NOD mice is most likely dependent on helper functions provided by CD4 T cells. However, even if their initial expansion in standard NOD mice is aided by helper factors, it is possible that in the preclinical stages of IDDM development, MHC class I-restricted clonotypes with AI4-like characteristics achieve a critical threshold level which could then allow them to independently mediate progression to overt disease. Under this scenario, once AI4-like effectors reach a certain threshold level, IDDM will still develop even if the activities of all MHC class II-restricted ß cell-autoreactive T cells are eliminated. This could be of great clinical significance since many envisioned IDDM intervention protocols are targeted at MHC class II-restricted autoreactive T cell responses. Given these concerns, it will be critical to have an understanding of the selection and activation requirements for MHC class I-restricted ß cell-autoreactive clonotypes such as AI4 that can independently mediate IDDM development.
Previously, most attention has focused on the way CD4 T cells interact
with unusual MHC class II variants to elicit IDDM in both humans and
NOD mice. However, the current study, combined with previous findings
from Verdaguer et al. (30), clearly indicate that under
some circumstances NOD mice can develop IDDM solely through the
interaction of CD8 T cells with very common MHC class I gene products
that do not contribute to autoimmunity when expressed in other strains.
Interestingly, there have been reports that certain common MHC class I
alleles are also associated with an increased risk for IDDM development
in humans (32, 33, 34, 35). Thus, an important future issue will
be to determine the mechanisms by which some common MHC class I
variants can acquire autoimmune diabetogenic functions when expressed
in certain individuals and NOD mice. The most likely scenario is that
normally nonpathogenic MHC class I variants can only acquire autoimmune
diabetogenic functions through interactions with some of the other
susceptibility genes located both within and outside the MHC. The
NOD.AI4ß Tg stock is likely to be invaluable in determining the
mechanisms by which a common MHC class I variant can acquire the
aberrant ability to select and functionally activate CD8 T cells
capable of independently mediating autoimmune IDDM. For example, it
could be outcrossed with IDDM-resistant strains congenic for the NOD
H2g7 MHC haplotype to map and identify non-MHC
genes that may contribute to selection of diabetogenic CD8 T cells.
AI4 represents the first example of a MHC class I-restricted CD8 T cell
with an ability to rapidly mediate IDDM development in NOD mice without
prior activation in vitro and in the total absence of helper
activities. We have found that AI4 T cells do not recognize the
Kd-restricted insulin peptide that is the
antigenic target of another NOD-derived ß cell-autoreactive CD8
clonotype (36). Furthermore, AI4 T cells do not recognize
the NRP mimotope of the Kd-restricted ß cell
autoantigen that is the target of the NY8.3 clone (37).
Given the greatly accelerated rate of IDDM development in the
NOD.AI4ß Tg stock, the MHC class I-restricted antigenic peptide
recognized by the AI4 TCR is likely to be of great pathological
significance. Thus, its identification could lead to the development of
tolerogenic therapies that inhibit IDDM development in NOD mice, which
might also be ultimately applicable to humans at risk for this
disease.
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Footnotes |
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2 Current address: Corixa Corp., 1124 Columbia Street, Suite 225, Seattle, WA 98104.
3 Address correspondence and reprint requests to Dr. David V. Serreze, The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609. E-mail address:
4 Abbreviations used in this paper: IDDM, insulin-dependent diabetes mellitus; PBL, peripheral blood leukocyte.
Received for publication November 2, 1999. Accepted for publication January 14, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-chain. Nature 345:727.[Medline]
-chain gene rearrangement. Proc. Natl. Acad. Sci. USA 95:12538. chains on the surface of T cells in T cell receptor transgenic mice. J. Exp. Med. 178:1807.This article has been cited by other articles:
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E. Enee, E. Martinuzzi, P. Blancou, J.-M. Bach, R. Mallone, and P. van Endert Equivalent Specificity of Peripheral Blood and Islet-Infiltrating CD8+ T Lymphocytes in Spontaneously Diabetic HLA-A2 Transgenic NOD Mice J. Immunol., April 15, 2008; 180(8): 5430 - 5438. [Abstract] [Full Text] [PDF]
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H. Tsui, Y. Chan, L. Tang, S. Winer, R. K. Cheung, G. Paltser, T. Selvanantham, A. R. Elford, J. R. Ellis, D. J. Becker, et al. Targeting of Pancreatic Glia in Type 1 Diabetes Diabetes, April 1, 2008; 57(4): 918 - 928. [Abstract] [Full Text] [PDF]
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R. Mallone, E. Martinuzzi, P. Blancou, G. Novelli, G. Afonso, M. Dolz, G. Bruno, L. Chaillous, L. Chatenoud, J.-M. Bach, et al. CD8+ T-Cell Responses Identify {beta}-Cell Autoimmunity in Human Type 1 Diabetes Diabetes, March 1, 2007; 56(3): 613 - 621. [Abstract] [Full Text] [PDF]
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Y.-G. Chen, P. A. Silveira, M. A. Osborne, H. D. Chapman, and D. V. Serreze Cellular Expression Requirements for Inhibition of Type 1 Diabetes by a Dominantly Protective Major Histocompatibility Complex Haplotype Diabetes, February 1, 2007; 56(2): 424 - 430. [Abstract] [Full Text] [PDF]
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D. V. Serreze, M. A. Osborne, Y.-G. Chen, H. D. Chapman, T. Pearson, M. A. Brehm, and D. L. Greiner Partial versus Full Allogeneic Hemopoietic Chimerization Is a Preferential Means to Inhibit Type 1 Diabetes as the Latter Induces Generalized Immunosuppression J. Immunol., November 15, 2006; 177(10): 6675 - 6684. [Abstract] [Full Text] [PDF]
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C. P. Wong, L. Li, J. A. Frelinger, and R. Tisch Early Autoimmune Destruction of Islet Grafts Is Associated with a Restricted Repertoire of IGRP-Specific CD8+ T Cells in Diabetic Nonobese Diabetic Mice J. Immunol., February 1, 2006; 176(3): 1637 - 1644. [Abstract] [Full Text] [PDF]
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T. M. Kupfer, M. L. Crawford, K. Pham, and R. G. Gill MHC-Mismatched Islet Allografts Are Vulnerable to Autoimmune Recognition In Vivo J. Immunol., August 15, 2005; 175(4): 2309 - 2316. [Abstract] [Full Text] [PDF]
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Y. Hassainya, F. Garcia-Pons, R. Kratzer, V. Lindo, F. Greer, F. A. Lemonnier, G. Niedermann, and P. M. van Endert Identification of Naturally Processed HLA-A2--Restricted Proinsulin Epitopes by Reverse Immunology Diabetes, July 1, 2005; 54(7): 2053 - 2059. [Abstract] [Full Text] [PDF]
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M. Ejrnaes, N. Videbaek, U. Christen, A. Cooke, B. K. Michelsen, and M. von Herrath Different Diabetogenic Potential of Autoaggressive CD8+ Clones Associated with IFN-{gamma}-Inducible Protein 10 (CXC Chemokine Ligand 10) Production but Not Cytokine Expression, Cytolytic Activity, or Homing Characteristics J. Immunol., March 1, 2005; 174(5): 2746 - 2755. [Abstract] [Full Text] [PDF]
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Y.-G. Chen, C.-M. Choisy-Rossi, T. M. Holl, H. D. Chapman, G. S. Besra, S. A. Porcelli, D. J. Shaffer, D. Roopenian, S. B. Wilson, and D. V. Serreze Activated NKT Cells Inhibit Autoimmune Diabetes through Tolerogenic Recruitment of Dendritic Cells to Pancreatic Lymph Nodes J. Immunol., February 1, 2005; 174(3): 1196 - 1204. [Abstract] [Full Text] [PDF]
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S. Hussain and T. L. Delovitch Dysregulated B7-1 and B7-2 Expression on Nonobese Diabetic Mouse B Cells Is Associated with Increased T Cell Costimulation and the Development of Insulitis J. Immunol., January 15, 2005; 174(2): 680 - 687. [Abstract] [Full Text] [PDF]
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E. J. Gordon, L. S. Wicker, L. B. Peterson, D. V. Serreze, T. G. Markees, L. D. Shultz, A. A. Rossini, D. L. Greiner, and J. P. Mordes Autoimmune Diabetes and Resistance to Xenograft Transplantation Tolerance in NOD Mice Diabetes, January 1, 2005; 54(1): 107 - 115. [Abstract] [Full Text] [PDF]
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S. M. Lieberman, T. Takaki, B. Han, P. Santamaria, D. V. Serreze, and T. P. DiLorenzo Individual Nonobese Diabetic Mice Exhibit Unique Patterns of CD8+ T Cell Reactivity to Three Islet Antigens, Including the Newly Identified Widely Expressed Dystrophia Myotonica Kinase J. Immunol., December 1, 2004; 173(11): 6727 - 6734. [Abstract] [Full Text] [PDF]
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C.-M. Choisy-Rossi, T. M. Holl, M. A. Pierce, H. D. Chapman, and D. V. Serreze Enhanced Pathogenicity of Diabetogenic T Cells Escaping a Non-MHC Gene-Controlled Near Death Experience J. Immunol., September 15, 2004; 173(6): 3791 - 3800. [Abstract] [Full Text] [PDF]
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T. Takaki, S. M. Lieberman, T. M. Holl, B. Han, P. Santamaria, D. V. Serreze, and T. P. DiLorenzo Requirement for Both H-2Db and H-2Kd for the Induction of Diabetes by the Promiscuous CD8+ T Cell Clonotype AI4 J. Immunol., August 15, 2004; 173(4): 2530 - 2541. [Abstract] [Full Text] [PDF]
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M. E. Pauza, C. M. Dobbs, J. He, T. Patterson, S. Wagner, B. S. Anobile, B. J. Bradley, D. Lo, and K. Haskins T-Cell Receptor Transgenic Response to an Endogenous Polymorphic Autoantigen Determines Susceptibility to Diabetes Diabetes, April 1, 2004; 53(4): 978 - 988. [Abstract] [Full Text] [PDF]
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D. V. Serreze, T. M. Holl, M. P. Marron, R. T. Graser, E. A. Johnson, C. Choisy-Rossi, R. M. Slattery, S. M. Lieberman, and T. P. DiLorenzo MHC Class II Molecules Play a Role in the Selection of Autoreactive Class I-Restricted CD8 T Cells That Are Essential Contributors to Type 1 Diabetes Development in Nonobese Diabetic Mice J. Immunol., January 15, 2004; 172(2): 871 - 879. [Abstract] [Full Text] [PDF]
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L. Wen, F. S. Wong, R. Sherwin, and C. Mora Human DQ8 Can Substitute for Murine I-Ag7 in the Selection of Diabetogenic T Cells Restricted to I-Ag71 J. Immunol., April 1, 2002; 168(7): 3635 - 3640. [Abstract] [Full Text] [PDF]
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D. V. Serreze, E. A. Johnson, H. D. Chapman, R. T. Graser, M. P. Marron, T. P. DiLorenzo, P. Silveira, Y. Yoshimura, S. G. Nathenson, and S. Joyce Autoreactive Diabetogenic T-Cells in NOD Mice Can Efficiently Expand From a Greatly Reduced Precursor Pool Diabetes, September 1, 2001; 50(9): 1992 - 2000. [Abstract] [Full Text] [PDF]
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D. K. Bishop, S. C. Wood, E. J. Eichwald, and C. G. Orosz Immunobiology of Allograft Rejection in the Absence of IFN-{{gamma}}: CD8+ Effector Cells Develop Independently of CD4+ Cells and CD40-CD40 Ligand Interactions J. Immunol., March 1, 2001; 166(5): 3248 - 3255. [Abstract] [Full Text] [PDF]
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C. E. Mathews, R. T. Graser, A. Savinov, D. V. Serreze, and E. H. Leiter Unusual resistance of ALR/Lt mouse beta cells to autoimmune destruction: Role for beta cell-expressed resistance determinants PNAS, January 2, 2001; 98(1): 235 - 240. [Abstract] [Full Text] [PDF]
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S. Kahl, M. Nissen, R. Girisch, T. Duffy, E. H. Leiter, F. Haag, and F. Koch-Nolte Metalloprotease-Mediated Shedding of Enzymatically Active Mouse ecto-ADP-ribosyltransferase ART2.2 Upon T Cell Activation J. Immunol., October 15, 2000; 165(8): 4463 - 4469. [Abstract] [Full Text] [PDF]
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, n = 14) or ß-chain (x,
n = 16) transgenes, or the two constructs together
(
, n = 10), were compared with that of
nontransgenic controls (
, n = 18).
