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,
Departments of
* Laboratory Medicine and Pathology and
Pediatrics and
Center for Immunology, University of Minnesota, Minneapolis, MN 55455
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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in the serum. Given that Ag expression in the thymus induced
development of T cells with dual TCR reactivity, and that dual-reactive
cells have been suggested to have autoimmune potential, we tested
whether they were a causal factor in the disease observed here. We
found that OT-I/K14-OVAp animals on a recombinase-activating
gene-deficient background still suffered from disease. In addition,
OT-I animals expressing OVA broadly in all tissues under a different
promoter did not experience disease, despite having a similar number of
dual-specific T cells. Thus, in this model it would appear that
dual-reactive T cells do not underlie autoimmune pathology. Finally, we
extended these observations to a second transgenic system involving 2C
TCR-transgenic animals expressing the SIY peptide Ag with the hK14
promoter. We discuss the potential relationship between autoimmunity
and self-Ags that are expressed in stratified
epithelium. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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There are numerous ways in which T cells with autoreactive receptors could escape clonal deletion in the thymus. T cells can modulate the level of surface molecules, such as the TCR, coreceptor, and CD5, to reduce their sensitivity and avoid deletion (5, 6, 7). T cells can also avoid deletion in the thymus by secondary TCR gene rearrangement, which occurs during allelic inclusion (8) and receptor editing (9). When the secondary gene rearrangement event occurs on the same allele as the primary, the primary TCR chain is replaced. When it occurs on the alternate allele it results in the synthesis of two TCR chains. In this later case, the second chain can compete with the first during pairing and assembly and thereby alter the T cell reactivity. T cells with two productive rearrangements of the same TCR chain are referred to as dual-reactive, even though one specificity may predominate.
Although receptor editing is viewed as a tolerance mechanism,
dual-reactive T cells have been shown to have autoimmune potential. In
one model, dual-reactive CD4+ T cells were
observed in mice that expressed a TCR transgene specific for an
influenza hemagglutinin along with the hemagglutinin Ag
(10). The Ag was expressed in hemopoietic cells with the
Ig 
promoter and in the pancreas with the rat insulin promoter.
Although the majority of hemagglutinin-specific T cells were deleted in
the thymus, CD4+ T cells that expressed the
transgenic TCR were detected in the peripheral lymphoid organs and the
pancreas. While these T cells were anergic when tested in vitro, 25%
of the mice developed mild diabetes. Adoptive transfer experiments
demonstrated that it was the CD4+ T cells that
expressed low levels of the transgenic -chain along with an
endogenously rearranged -chain that induced diabetes. In another
system, constitutive expression of two transgenic TCRs allowed T cells
to escape deletion in the thymus (11). These cells were
tolerant in the periphery but could be activated in vitro through
either TCR. These experiments suggest that dual-reactive T cells may
play a dominant role in induction of spontaneous autoimmune disease
(12).
We previously reported a TCR-transgenic strain where expression of
self-Ag in the thymus resulted in receptor editing. These mice
expressed the OT-I TCR, specific for a peptide epitope from
OVA in the context of the Kb MHC molecule. When
the OVA peptide Ag was expressed in the thymus under the human keratin
14 (K14)3 promoter,
only a modest reduction in thymic
CD4+CD8+ double positive
cells was observed. TCR gene rearrangement was highly
elevated in these precursors, and the predominant T cell population
that matured expressed both the transgenic receptor and an endogenous
TCR chain. Surprisingly, OT-I/K14-OVAp animals exhibited a lethal
disease between 2 and 6 wk of age. In this report we describe the
features of this disease and provide evidence that it is a CD8-mediated
autoimmune disease with significant manifestation in the skin. Because
of the large dual-reactive T cell population in these mice, and because
such cells have previously been reported to have autoimmune potential,
we tested the hypothesis that dual-reactive T cells play a dominant
role in spontaneous disease induction in this model.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C57BL/6 (B6) and RAG1null.B6 mice were
obtained from The Jackson Laboratory (Bar Harbor, ME). OT-I mice
express a transgenic receptor specific for the
OVA257–264 peptide (OVAp) in the context of the
H-2Kb (13). 2C mice
(14) express an alloreactive receptor that also has
reactivity to a synthetic peptide (SIYRYYGL), in the context of
H-2Kb (15). K14-OVAp and K14-SIYp
transgenic constructs were generated using a multistep PCR procedure as
previously described (16). Act-mOVA mice were obtained
from B. Ehst and M. Jenkins (University of Minnesota, Minneapolis, MN).
These mice express a transmembrane form of OVA under control of the
-actin promoter and CMV immediate-early enhancer. OVA could be
detected on the surface of all white blood cells by flow cytometry with
an OVA-specific Ab (Sigma-Aldrich, St. Louis, MO) and in all tissues by
immunohistochemistry (data not shown). All four major thymic APCs
(cortical and medullary epithelial cells, dendritic cells, and
macrophages) from Act-mOVA mice were able to stimulate OT-I T cells
(data not shown). All mice were treated in accordance with federal
guidelines approved by the University of Minnesota Institutional Animal
Care and Use Committee.
Flow cytometric analysis of lymphoid organs
Thymus, lymph nodes, and spleen were harvested from the
indicated mice between 2 and 8 wk of age and stained with Abs to CD4
(L3T4, RMA-5), CD8 (53-6.7), CD69 (H1.2F3), Thy 1.1 (HIS51), and TCR
(H57-597), all obtained from BD PharMingen (San Diego, CA).
V5 (MR9.1)- and V2 (B20.1.1)-specific Abs were used to detect the
OT-I transgene, although it should be noted that these Abs also
recognize endogenous V5 and V2 TCR chains. A clonotype-specific
Ab (1B2) was used to detect the 2C receptor along with an Ab to V8
(F23.1). Data were collected using a FACSCalibur (BD Biosciences, San
Jose, CA) and analyzed with FlowJo software (TreeStar, San Carlos,
CA).
Histology
Tissues from OT-I/K14-OVAp or OT-I control animals were arranged in aluminum foil cups, snap-frozen in liquid nitrogen, and stored at -80°C. Cryosections were cut 5 mm thick, mounted onto glass slides, fixed for 5 min in acetone, and stained with H&E.
Serum cytokine measurement
Serum was tested in duplicate with TNF- or IL-1 ELISA kits
(R&D Systems, Minneapolis, MN) according to the manufacturer’s
protocol. A standard curve was generated with known amounts of cytokine
provided in the kit, and the values in the serum were
extrapolated from this.
Ab treatment
Mice were injected i.p. with depleting Abs to CD8 (2.43),
CD8 (H35-17), or rat Ig beginning at day 1 after birth and
continuing every other day until 6 wk of age. An initial dose of 50
µg was increased to 100 µg after 2 wk of age and to 150 µg after
4 wk. A neutralizing Ab to TNF- (TN3-19.12; a gift of K. Sheehan,
Washington University, St. Louis, MO) was injected i.p. every fourth
day from birth to wk 1 (50 µg), from wk 1 to wk 3 (100 µg), and
from wk 3 to wk 6 (150 µg). All mice were weighed and monitored for
signs of disease every other day. Mice remaining at the end of wk 6
were sacrificed. Serum was taken for analysis as described above. Lymph
node and spleen were analyzed for T cell depletion by flow cytometry.
Depletion >95% was observed in all animals.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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gene rearrangement occurred
(9). This receptor editing was required for efficient
development of mature T cells. Thus, a significant number of CD4 and
CD8 T cells were present in periphery of OT-I/K14-OVAp mice
(Table I
). These cells expressed the
transgenic TCR chain (V5) at a high level and the transgenic
-chain (V2) at a reduced level (9), implying the
usage of an endogenous TCR chains. Interestingly, the level of V2
on CD8 T cells from the spleen or lymph nodes of OT/K14-OVAp mice was
consistently higher than the level of V2 on mature CD8 thymocytes in
the same animals (Fig. 1A). In
addition, the cell surface phenotype of CD8 T cells from OT-I/K14-OVAp
animals differed from control OT-I animals, being
CD44high, CD62Llow, and
CD69+ (9). Together these features
suggest that peripheral CD8 T cells in OT-I/K14-OVAp mice were
activated.
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OT-I/K14-OVAp double transgenic animals experienced a lethal
disease. The outward signs included hair loss, skin lesions, weight
loss, and a hunched appearance (Fig. 2).
Disease was not observed in OT-I or K14-OVAp single transgenic
littermates (Fig. 3A and data
not shown). Onset occurred at an average age of 2–4 wk and was
incompletely penetrant, with 20% of animals showing no signs of
disease (Fig. 3A). Animals with outward signs of the disease
showed, on average, higher levels of TNF- in the serum (Fig. 4). In addition, the level of TNF- in
the serum was elevated in a few of the double transgenic mice that were
not acutely ill. However, there were no major differences in cellular
composition or T cell surface phenotype of lymph node and spleen cells
from acutely sick double transgenics and age-matched littermates that
showed no signs of disease (data not shown).
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). This infiltrate
consisted of CD4 T cells, CD8 T cells, and macrophages, but not B cells
(data not shown). Hyperkeratosis and sloughing were observed in some
areas of the skin. In the esophagus (Fig. 5) and tongue (data not
shown), inflammation was again localized to the epithelial layer.
Double transgenic animals showed occasional incidence of diarrhea and
intestinal necrosis. However, this was not a consistent feature of this
disease and in most animals the epithelium of the stomach, small
intestine, and colon appeared intact, with no significant mononuclear
cell infiltrate. Transgenes driven by the hK14 promoter were shown to
be expressed in a manner similar to endogenous K14, specifically in
basal cells of stratified epithelium in skin, esophagus, and tongue
(17, 18, 19, 20, 21). Therefore, the pattern of infiltration
reproducibly observed in skin and esophagus is consistent with the
predicted Ag expression pattern in these animals. We also observed an
inflammatory infiltrate in the liver (Fig. 5). The infiltrate was not
observed in the parenchyma of the liver or around hepatic venules, but
surrounded the bile duct. Although transgene expression was not
detected in total liver RNA by PCR (9), it was detected in
RNA from bile duct (data not shown), perhaps explaining the unique
pattern of infiltration in this organ. Nonetheless, bile duct was not
obliterated and function was not impaired, at least as reflected by the
normal levels of bilirubin and 
-glutamyl transpeptidase
present in the serum (data not shown). In skin, esophagus, and liver,
the composition of the infiltrate was similar, being comprised of both
CD4 and CD8 T cells and macrophages but not B cells (data not shown).
Other organs that were analyzed and appeared normal included heart,
lung, pancreas, and kidney (data not shown).
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T cells
The activated phenotype of the CD8 T cells and the fact that there
was a mononuclear cell infiltrate found in areas of Ag expression
suggested that the disease in the OT-I/K14-OVAp mice might be due to
the autoaggressive CD8 T cells. To test this, CD8 T cells were depleted
with administration of Abs to CD8 or CD8 from birth to 6 wk of
age. As a control, littermates were injected with rat Ig, and the mice
were monitored for signs of disease. All mice injected with CD8 Abs
survived, whereas only 3 of the 10 mice injected with the control Ab
survived (Table II). The percentage of
survival in mice injected with the control Ab was similar to untreated
OT-I/K14-OVAp mice. Thus, CD8 T cells are required for disease
induction.
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homodimers could mature extrathymically in TCR-transgenic mice
(22, 23). FACS analysis of the spleen and lymph nodes from
OT-I/K14-OVAp mice indicated that there was only a very small increase
in CD8 cells, but that these cells also had an activated
phenotype (data not shown). To test whether it was these cells or
conventional CD8 heterodimer expressing T cells of thymic origin
that induced disease, we treated mice with a CD8 Ab. Similar to the
CD8 depletion, all of the mice injected with the CD8 Ab survived,
indicating that the CD8 T cells alone did not cause disease. Mice
depleted with either CD8 or CD8 Ab did not display elevated
levels of TNF in the serum (data not shown). Because of the correlation
between elevated levels of TNF- and disease, we also tested whether
TNF- was required for disease. Six OT-I/K14-OVAp mice were injected
with a neutralizing Ab to TNF- (24), beginning at day 1
after birth and continuing every 4 days until 6 wk of age.
Surprisingly, five of the six mice suffered from acute disease and died
by 6 wk of age (Table II
). This indicated that, while TNF- levels
were high in acutely sick mice, this cytokine was not the sole mediator
of disease. In this regard, we noted that IL-1 was elevated in seven
of nine serum samples from acutely ill mice (Fig. 4B);
therefore, it is possible that IL-1 could mediate inflammation in
TNF- neutralized mice. Disease was not dependent on dual-reactive T cells
Because it was previously shown that T cells with two TCRs could
induce autoimmune disease, and because the majority of CD8 T cells in
these animals express two receptors, we wanted to test the role of
dual-reactive T cells in disease induction in this model. To do this,
we crossed the OT-I/K14-OVAp mice to the recombinase-activating gene
(RAG)1null background. In the absence of RAG1
protein, rearrangement of endogenous TCRs cannot occur, thereby
eliminating dual-reactive T cells. As shown previously, this
dramatically limited the development of CD8 T cells in the thymus
(9). Nevertheless, some T cells were present in the
periphery of the OT-I/K14-OVAp RAGnull mice
(Table I), and these cells expressed the OT-I TCR and CD8, albeit at
levels slightly lower than controls (Fig. 1B). Fig. 3 shows
that these mice also suffered from acute disease, indicating that dual
reactivity is not required. However, the disease in the OT-I/K14-OVAp
RAGnull mice was delayed in the time of onset
compared with the double transgenics on a wild-type background (Fig. 3A). The symptoms of the disease were similar to wild-type
OT-I/K14-OVAp mice including hair loss, skin lesions, and weight loss.
There were also elevated levels of TNF- in the serum of the
OT-I/K14-OVAp RAGnull mice, but the levels on
average were not as high as the OT-I/K14-OVAp mice on a wild-type
background (Fig. 4). These data show that T cell dual reactivity is not
required for cells to escape deletion in the thymus or to induce
autoimmune disease in this model.
Not only are dual-reactive T cells dispensable for disease, but data
from a second Ag transgenic we studied suggests that dual
receptor-expressing T cells are not sufficient to induce disease
either. In this case we obtained transgenic mice where an actin
promoter was used to drive OVA expression at a high level in all
tissues (Act-mOVA). Interestingly, a thymic phenotype consistent with
receptor editing was observed in this mouse, as in OT-I/K14-OVAp mice
(D. Mayerova and K. A. Hogquist, manuscript in preparation). The
thymus and spleen showed a large number of CD4 and CD8 T cells with
low-level expression of the transgenic -chain (Fig. 1A
and Table I). The transgenic -chain was not decreased, indicating
endogenous TCR chain usage. Nonetheless, these mice were completely
healthy (Fig. 3B), again suggesting that autoimmune disease
in OT-I/K14-OVAp is not a reflection of receptor editing. In Fig. 1A, note that CD8 T cells from both thymus and lymph node of
OT-I/Act-mOVA mice expressed a very low level of the transgenic
-chain and had not up-regulated CD69. However, peripheral CD8 T
cells from OT-I/K14-OVAp always expressed a higher level of V2 than
CD8 thymocytes from the same mice, although this level was not as high
as CD8 T cells expressing only the transgenic - and -chains. This
up-regulation on peripheral cells might be a result of T cell
activation to the K14-OVAp Ag. Indeed, the CD69+
CD8 T cells seen in OT-I/K14-OVAp are predominantly among this higher
V2-expressing subset (data not shown). These results suggest that
disease may be associated with Ags expressed under control of the hK14
promoter rather than with receptor editing as a tolerance
mechanism.
To test whether Ag expression by K14 results in disease in other
TCR-transgenic models, we studied the 2C TCR-transgenic strain. The 2C
TCR recognizes the peptide mimetope SIYRYGGL when presented by
H-2Kb (15). We created transgenic
mice expressing this peptide under the control of the human K14
promoter. In the thymus of 2C/K14-SIY mice there was a profound
reduction in the number of
CD4+CD8+ precursor cells
and no significant receptor editing at the TCR locus, in
contrast to that observed in OT-I mice (D. Mayerova and K. A.
Hogquist, manuscript in preparation). The small number of CD8 T cells
in the thymus, as well as those in the spleen, expressed both the
transgenic - and -chains of the 2C receptor (Fig. 1). Despite the
small number of CD8 T cells maturing in the thymus, 2-wk-old mice
displayed a significant number of CD8 T cells in the spleen (Table I).
These cells were apparently able to initiate disease, because these
mice suffered from a similar lethal disease to the OT-I/K14-OVAp strain
(Fig. 3B). Altogether, these data suggest that the K14
promoter results in an Ag expression pattern or level that is difficult
to achieve complete immunological tolerance to. The breakdown of
tolerance in this case does not correlate with the extent of clonal
deletion or receptor editing in the thymus and may reflect a breakdown
in an as-yet-unidentified peripheral tolerance process.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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observed in the serum of these mice might
account for the lethality, because aspects of this disease are similar
to those seen in mice expressing TNF- as a transgene
(20). Nonetheless, serum levels of TNF- varied, and a
TNF- neutralization treatment did not prevent lethal disease.
IL-1 and IL-1 were also elevated in double transgenics (Fig. 4),
and in the absence of TNF- these cytokines might contribute to
disease. Thus, disease initiation does not require TNF-, and the end
stages of the disease process could involve multiple factors including
TNF-. CD8 T cells were required for the disease, because treatment
with Ab to either CD8 or CD8 prevented lethality and no disease
characteristics were observed in treated animals.
T cells with dual TCR reactivity were previously shown to have
autoimmune potential (10, 11). Because the OT-I/K14-OVAp
animals showed a high number of dual-reactive CD8 T cells, we
considered whether this was a factor in disease induction.
OT-I/K14-OVAp animals on a RAGnull background
still experienced disease, although the average age of onset was
delayed by 
4 wk. This experiment formally proved that dual-reactive
T cells are not required for disease. However, the delayed onset of
disease in RAGnull animals might suggest that
dual-reactive T cells can accelerate or exacerbate disease. However,
such a conclusion would be premature, because
RAGnull animals also have a B cell deficiency,
severe lymphopenia, and a greatly reduced total number of CD8 T cells.
Such factors could also contribute to the age of disease onset. The
study of TCRnull double transgenics and
development of an adoptive transfer system to mimic disease are being
used to approach this issue further.
The lack of correlation between the number of dual-reactive T cells and
disease occurrence in two additional strains we examined also suggested
that dual reactivity was not a key factor in this model of autoimmune
disease. OT-I/Act-mOVA animals had a slightly higher number of dual
receptor-expressing CD4 and CD8 T cells in the spleen compared with
OT-I/K14-OVAp animals (Fig. 1 and Table I). However, this strain showed
no signs of disease. The fact that OT-I/K14 and OT-I/mOVA strains had a
similar thymic tolerance phenotype but differed absolutely in disease
occurrence suggests that the immune dysregulation in OT-I/K14 may be
related to how or where the Ag is presented in the peripheral tissues
of K14 mice. Consistent with this, we also observed disease in 2C
animals expressing Ag under control of the human K14 promoter. Thymic
tolerance (via clonal deletion) was very profound and these animals
matured few CD8 T cells in thymus, similar to 2C animals expressing
Ld (14). Thus again, the disease
incidence did not correlate with thymic tolerance, at least in terms of
whether clonal deletion or receptor editing was more predominant. In
other TCR-transgenic models of spontaneous autoimmune disease 1) thymic
tolerance did not occur (25), 2) deletion occurred but was
partial (26), 3) deletion occurred and was profound
(10), or 4) allelic inclusion allowed selective maturation
of cells with dual reactivity (10). Thus, a breakdown of
clonal deletion does not appear to correlate with spontaneous disease
in other transgenic models.
Recent studies suggest that the thymus also directs the selection of regulatory CD25+CD4+ T cells (27). A potential deficiency of thymus-derived regulatory CD4 T cells in the above models has not been addressed. In our model, we might consider the possibility that Ags expressed under the K14 promoter do not efficiently select regulatory CD25+CD4+ T cells in the thymus. Such cells have recently been shown to suppress CD8 T cell responses (28). In light of this possibility, it is interesting that class II molecules expressed under the control of the K14 promoter did allow selection of CD25+ regulatory CD4 T cells (29). However, in our case, where the transgene encodes only the 8-aa class I binding peptide, this would not be sufficient to select class II-restricted, OVA-specific regulatory CD4 T cells. Nonetheless, it is unlikely that this would be the sole factor contributing to disease in this situation. If the absence of Ag-specific regulatory CD4 T cells resulted in disease, then disease should be a universal feature of all transgenic animals expressing class I binding peptide minigenes. Two other articles describing peptide transgenic mice did not report health problems, even when crossed to TCR transgenics specific for the Ag (30, 31).
Based on the data presented in this work, it is possible that use of the K14 promoter to express self-Ags is associated with the breakdown of peripheral tolerance. We note with interest that the localization of hK14-driven transgenes correlates rather tightly with that of the specialized subset of dendritic cells termed Langerhans cells (LC). These cells reside specifically in stratified epithelial tissue, including the epidermis, hair follicle, and esophagus (32). Within the epidermis, LC form a semicontinuous network directly underneath the basal cell layer of keratinocytes. LC become activated and migrate to the lymph node during skin irritation, injury, or infection. Of APCs, LC represent a likely candidate APC for the presentation of OVAp to lymph node T cells in OT-I/K14-OVAp mice, although this remains to be tested directly. Thus, it is interesting to consider whether skin injury or infection might be a cofactor for disease induction or escalation in this murine autoimmune disease model. Perhaps in the context of other predisposing factors, peripheral tolerance more frequently fails to control the T cell response to self-Ags that are repeatedly or chronically presented by APC from the skin but not from other tissues. Skin injury has been shown to lead to pathologic lesions in individuals predisposed to the human autoimmune disease psoriasis—a phenomenon referred to as Koebner’s effect (33).
A predisposing factor in this model is clearly the high Ag-specific T cell clone frequency. We emphasize that both K14-OVAp and K14-SIYp single transgenic animals appear healthy and viable; disease was observed only after crossing K14 transgenic animals to a TCR-transgenic specific for the Ag. This is consistent with CTL tolerance to a viral Ag driven by the K14 promoter, observed in a non-TCR-transgenic system (34). Thus, an exaggerated frequency or continued onslaught of T cells may be required to shift the tolerance/immunity balance in this model, as in all TCR-transgenic models of spontaneous disease (10, 35, 36, 37, 38, 39). In humans, expansion of T cell clones occurs during the immune response (40, 41) and under conditions of lymphopenia (42, 43). However, it is not clear whether this is a predisposing factor in human autoimmune disease (44). Because of this, murine TCR-transgenic models may not represent ideal systems to study the basis of immune tolerance loss. Nonetheless, TCR transgene-based models of autoimmune disease can potentially be useful to define pathogenic processes and autoimmune spreading mechanisms, and to test treatment protocols. Future experiments will be aimed at determining the potential roles of skin injury in disease induction and escalation in this model.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Kristin A. Hogquist, Department of Laboratory Medicine and Pathology, University of Minnesota, Box 334, 420 Delaware Street SE, Minneapolis, MN 55455. E-mail address: hogqu001{at}umn.edu
3 Abbreviations used in this paper: K14, human keratin 14; RAG, recombinase-activating gene; LC, Langerhans cell.
Received for publication March 4, 2002. Accepted for publication June 11, 2002.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and T cell receptor alleles. Cell 69:529.[Medline]
genes poses an autoimmune hazard due to low-level expression of autospecific receptors. Immunity 8:563.[Medline]
bypasses the need for c-Ha-ras mutations in mouse skin tumorigenesis. Mol. Cell. Biol. 12:4643. transgenic mice. Genes Dev. 6:1444./ co-receptors by self-antigen in the murine gut. Proc. Natl. Acad. Sci. USA 89:5336./ in the intestinal epithelium. J. Exp. Med. 178:1947.This article has been cited by other articles:
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  C. D. Hammerbeck and M. F. Mescher Antigen Controls IL-7R{alpha} Expression Levels on CD8 T Cells during Full Activation or Tolerance Induction J. Immunol., February 15, 2008; 180(4): 2107 - 2116. [Abstract] [Full Text] [PDF]
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W. Liu, D. P. Evanoff, X. Chen, and Y. Luo Urinary Bladder Epithelium Antigen Induces CD8+ T Cell Tolerance, Activation, and Autoimmune Response J. Immunol., January 1, 2007; 178(1): 539 - 546. [Abstract] [Full Text] [PDF]
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D. Mayerova, L. Wang, L. S. Bursch, and K. A. Hogquist Conditioning of langerhans cells induced by a primary CD8 T cell response to self-antigen in vivo. J. Immunol., April 15, 2006; 176(8): 4658 - 4665. [Abstract] [Full Text] [PDF]
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 D. Mustacich, A. Wagner, R. Williams, W. Bair, L. Barbercheck, S. P. Stratton, A. K. Bhattacharyya, and G. Powis Increased skin carcinogenesis in a keratinocyte directed thioredoxin-1 transgenic mouse Carcinogenesis, October 1, 2004; 25(10): 1983 - 1989. [Abstract] [Full Text] [PDF]
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 F. F. Shih, L. Mandik-Nayak, B. T. Wipke, and P. M. Allen Massive Thymic Deletion Results in Systemic Autoimmunity through Elimination of CD4+ CD25+ T Regulatory Cells J. Exp. Med., February 2, 2004; 199(3): 323 - 335. [Abstract] [Full Text] [PDF]
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D. Mayerova and K. A. Hogquist Central Tolerance to Self-Antigen Expressed by Cortical Epithelial Cells J. Immunol., January 15, 2004; 172(2): 851 - 856. [Abstract] [Full Text] [PDF]
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 E. R. Sherwood, C. Y. Lin, W. Tao, C. A. Hartmann, J. E. Dujon, A. J. French, and T. K. Varma {beta}2 Microglobulin Knockout Mice Are Resistant to Lethal Intraabdominal Sepsis Am. J. Respir. Crit. Care Med., June 15, 2003; 167(12): 1641 - 1649. [Abstract] [Full Text] [PDF]
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 L. Fan, B. W. Busser, T. Q. Lifsted, D. Lo, and T. M. Laufer Antigen presentation by keratinocytes directs autoimmune skin disease PNAS, March 18, 2003; 100(6): 3386 - 3391. [Abstract] [Full Text] [PDF]
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