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*
Department of Immunology and Infectious Diseases, Harvard School of Public Health, and
Department of Medicine, Harvard Medical School, Boston, MA 02115
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Positive selection of CD4+ T cells requires that the TCR of a developing thymocyte interact productively with self-MHC class II molecules on thymic cortical epithelium (9, 10, 11). Only cortical epithelium can do this; neither medullary epithelium (12) nor hemopoietic elements (13) can mediate this process in vivo. The exact tissue requirements for the opposing process of negative selection are more controversial. Immunohistochemical analyses suggest that negative selection occurs at the corticomedullary junction (14) and within the thymic medulla (15). At these sites, the majority of clonal deletion is induced by interactions between self-reactive thymocytes and hemopoietic APCs (10, 16). The role of cortical and medullary epithelium in clonal deletion is more complex. Medullary epithelium can induce clonal deletion and subsequent tolerance (17, 18). Studies using MHC class II transgenic mice have demonstrated that medullary epithelium can delete superantigen-specific CD4+ T cell precursors (19). However, Miller’s group suggested that thymic medullary epithelium could not induce complete tolerance to a MHC class I-restricted self Ag. Low affinity cells could not cause skin graft rejection in vivo despite displaying in vitro self reactivity in a CTL assay (20). Thus, thymic medullary epithelium can tolerize both CD4+ and CD8+ T cell populations, although less efficiently than bone marrow-derived dendritic cells.
The role of thymic cortical epithelium in negative selection continues to be debated. Other groups have suggested that certain self-reactive transgenic TCRs could be deleted in either thymic organ culture (21) or reaggregate culture (22) upon encountering their nominal Ag expressed on thymic cortical epithelium. Additionally, thymic cortical epithelium can induce the deletion of self-reactive T cell precursors in vitro (23, 24). However, we previously generated K14 mice in which an I-Ab transgene is expressed only on thymic cortical epithelium and demonstrated that such mice could not mediate negative selection to superantigen, endogenous self Ag, or exogenous foreign Ag (25).
CD4+ T cells selected in the K14 thymus are autoreactive in vitro; they proliferate to and kill I-Ab-positive target cells (25). The K14 mice are healthy and show no evidence of autoimmunity despite the presence of autoreactive CD4+ T cells. This is expected, since there are no MHC class II molecules expressed on peripheral APC to activate the self-reactive CD4+ T cells. It was possible, however, that similar to medullary epithelium, cortical epithelium might tolerize CD4+ T cells, resulting in in vitro reactivity in the absence of in vivo activity. To examine in vivo reactivity requires adoptive transfer of the selected CD4+ T cells into class II-positive hosts. If tolerance has occurred in K14 mice, then these CD4+ T cells would not be expected to be pathogenic upon transfer to wild-type syngeneic mice. Here we describe two distinct adoptive transfer systems that demonstrate that K14-derived CD4+ T cells are not tolerized and can cause autoimmune disease in class II-expressing hosts.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The B6, BALB/c, and AKR mice were purchased from Taconic Farms (Germantown, NY). The bm12 mice were purchased from The Jackson Laboratory (Bar Harbor, ME). The Aßb-/- mice (class II negative) have been described previously (26). The Aßb-/- mice used in these experiments had been backcrossed to B6 mice between 12 and 17 times. The K14 mice (25) were backcrossed to B6 mice 13 times. All mice were maintained pathogen free in a barrier facility.
Flow cytometry
Cells were analyzed on a Becton Dickinson FACSCalibur using
CellQuest software (Becton Dickinson, Mountain View, CA). The following
Abs were purchased from PharMingen (San Diego, CA): CD3
(145-2C11),
CD4 (RM4-5), B220 (RA3-6B2), I-Ab (AF6-120.1),
V
2 (B20.1), V3.2 (RR3-16),
V8 (B21.14), V11 (RR8-1),
Vß2 (B20.6), Vß3 (KJ25), Vß4
(KT4), Vß5 (MR9-4), Vß6 (RR4-7),
Vß8 (MR5-2), Vß9 (MR10-2),
Vß10 (B21.5), Vß11 (RR3-15),
Vß12 (MR11-1), Vß13 (MR12-3), and
Vß14 (14-2).
Production and analysis of T hybrids
Splenocytes from K14 mice were stimulated for 3 days in bulk
culture with irradiated B6 splenocytes at a ratio of 2.5:1. Blasts were
purified on Lympholyte-M (Cedarlane Laboratories, Hornby, Canada)
gradients, washed, fused to BW5147-ß- (27) and selected
for hypoxanthine-aminopterin-thymidine resistance. B6-reactive hybrids
were subsequently single-cell cloned; this was verified by
Vß FACS staining. MHC reactivities were assessed by
culturing 1 x 105 T cell hybrids with 4 x
105 unirradiated splenocytes from mice of the given MHC in
200 µl for 24 h. (Preliminary experiments showed that
irradiation of the stimulator splenocytes had no effect on IL-2
production by the hybridomas.) After 24 h, 100 µl of culture
supernatant was removed and assayed for IL-2 production using the
indicator cell line, HT-2 (28) Hybrids were graded as positive when the
stimulation index exceeded background (with class
II-/- stimulators) by at least twofold.
CD4+ T cell purification
CD4+ T cells were purified from spleen and lymph node of K14, B6, or bm12 mice. Single cell suspensions were plated on petri dishes coated with 25 µg/ml goat anti-mouse IgG (Cappel Laboratories, Durham, NC). Nonadherent cells were stained with anti-CD4 Ab and purified on paramagnetic MiniMACS columns according to the manufacturer’s instructions (Miltenyi Biotec, Auburn, CA). The final population of B6 or bm12 CD4+ T cells was always >95% pure; K14 CD4+ T cells were routinely >90% pure.
Acute GVHD (AGVHD)4
AGVHD was induced in male B6 mice, aged 8–10 wk. Bone marrow cells were aspirated from the femurs and tibias of C57BL/6 mice and depleted of T cells by incubation with anti-Thy1.2 mAb (AT83A supernatant) at a 1/5 dilution at 4°C for 30 min followed by Low-Tox M rabbit complement (Accurate Chemicals, Westbury, NY) at a 1/20 dilution at 37°C for 45 min. Host mice were irradiated with a single dose of 900 rad using a cobalt source and injected i.v. with 1 x 107 T-depleted bone marrow cells and either 2 x 105 or 2 x 106 CD4+ T cells. Mice were maintained with ad libitum food and acidified water (pH 1.3–2). Mice were sacrificed if moribund (unable to take food and water). Statistical analysis was completed using a log-rank test for equality of survivor function.
Chronic GVHD (CGVHD)
CGVHD was induced in male B6 mice, aged 8–10 wk. Recipient mice were injected i.v. with either 1 x 106 or 1 x 107 donor CD4+ T cells and then maintained in the barrier facility. Serum samples were obtained 8, 13, and 17 wk after T cell injection. Urine protein concentrations were checked at 2-wk intervals using Uristix reagent strips (Bayer, Elkhart, IN).
Anti-nuclear Ab detection
HepG2 cells were cultured overnight on coverslips. Cells were fixed with 3% formaldehyde, permeabilized with PBS containing 0.1% Triton-X, and blocked with a 1/300 dilution of donkey serum (Jackson ImmunoResearch Laboratories, West Grove, PA). Mouse serum was incubated on the slides at a 1/40 dilution and developed with indocarbocyanine-labeled donkey anti-mouse Ig (Jackson ImmunoResearch Laboratories).
Anti-ssDNA ELISAs
Flat-bottom 96-well microtiter plates were coated with heat-denatured calf thymus DNA (Sigma; 50 µg/ml) overnight at 4°C, blocked at room temperature with 1% gelatin, and incubated with serially diluted serum. Plates were developed by the addition of alkaline phosphatase-conjugated goat anti-mouse IgG followed by the addition of p-nitrophenyl phosphate and were read at A405. Samples were compared with standard curves of mIgG (Southern Biotechnology Associates, Birmingham, AL).
IgG levels
Plates were coated with unlabeled goat anti-mouse Ig (Southern Biotechnology Associates) and blocked with 2% BSA in borate buffered saline, and serial dilutions of serum were added. Plates were then developed by adding alkaline phosphatase-conjugated goat anti-mouse IgG (Southern Biotechnology Associates) and p-nitrophenyl phosphate. Samples were compared with standard curves of mIgG.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We previously noted that CD4+ T cells that interact with MHC class II-selecting ligands expressed only on thymic cortical epithelium use TCR Vß segments in a pattern that mirrors that of wild-type C57BL/6 mice (25). However, initial precursor frequency calculations suggested that only 5% of peripheral CD4+ T cells proliferated in response to syngeneic APC. Thus, it was necessary to isolate this population of autoreactive cells to look at its reactivity directly. We therefore produced a panel of self-reactive T cell hybrids from the K14 CD4+ T cells and examined the TCR usage and specificity of the autoreactive response.
Total splenocytes from a naive K14 mouse were activated in vitro for 3
days with irradiated syngeneic B6 APC, and blasts were fused with the
partner BW5147-ß-. T cell hybrids were obtained that
produced IL-2 in response to B6 APC, and 40 of these were subcloned for
further analysis.
To determine the MHC reactivities of the T cell hybrids, the cells were
incubated for 24 h with splenic APC from B6 (I-Ab),
AKR (I-Ak, I-Ek), or BALB/c (I-Ad,
I-Ed) mice, and the amount of IL-2 produced was quantified
by growth of the cytokine-dependent indicator line, HT-2 (Table I
). The
T cell response was class II dependent, as no hybrid analyzed produced
IL-2 upon stimulation with class II-negative
(Aßb-/-) APC. As summarized in Table II,
the T cell hybrids can be divided
into three classes, reflecting the pattern of APC to which the hybrids
respond. Thus, almost half the hybrids produced IL-2 on activation only
with B6 APC. Approximately one-third of the hybrids responded to both
B6- and AKR-derived APC, and the remainder responded to all three
haplotypes, B6, AKR, and BALB/c APC. Of note, no hybrid produced IL-2
upon stimulation with SJL (I-As) APC (not shown). The
amount of IL-2 produced by an individual promiscuous (responding to
more than one haplotype) hybrid stimulated by B6 APC was almost always
greater than that elicited by either AKR or BALB/c APC.
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and Vß usage of
the hybrids was determined by a combination of flow cytometry and PCR.
The hybrids analyzed use a broad spectrum of both V and
Vß genes (Table I
), and V genes did not appear to be
preferentially used by one class of hybrids. Thus, the autoreactive
CD4+ T cells that mature in the K14 mouse on thymic
cortical epithelium are a polyclonal population with polyclonal
reactivity. Polyclonal autoreactive K14 CD4+ T cells cause AGVHD
K14 CD4+ T cells are autoreactive in vitro; they proliferate to and kill I-Ab-positive targets (25). Having confirmed that this autoreactive population of K14 CD4+ T cells was polyclonal in vitro, we sought to determine whether the cells were also functional in vivo by asking whether they caused disease due to their reactivity with self class II.
AGVHD can be caused by transferring small numbers of donor T
cells to heavily irradiated class II-disparate mice reconstituted with
host bone marrow. Mortality results from the destruction of host class
II-positive hemopoietic cells, including stem cells, and failure of
engraftment (29). In this model of acute graft rejection, wild-type
C57BL/6 (B6) mice were lethally irradiated (900 cGy) and reconstituted
with 107 T cell-depleted B6-derived bone marrow and either
2 x 105 or 2 x 106 mature
CD4+ T cells derived from various strains. Table III shows the results of acute GVHD
experiments in which mice were reconstituted with B6 bone marrow and
either B6 CD4+ T cells or allogeneic class II-disparate
bm12 CD4+ T cells or K14-derived CD4+ T cells.
As expected, transfer of allogeneic bm12 CD4+ T cells led
to rapid death (average = 15 days with 2 x
106 T cells and 24 days for two mice treated with 2 x
105 T cells) due to failure of the B6 bone marrow to
engraft. In contrast, mice treated with syngeneic B6 CD4 T cells
recovered fully and survived >250 days. Impressively, mice treated
with 2 x 106 K14 CD4+ T cells succumbed
to acute GVHD in 12–13 days, a much more rapid time course than any
previously described. Indeed, as few as 2 x 105 K14
CD4 cells were also sufficient to induce AGVHD with a significantly
more rapid time course than that mediated by bm12 cells. Thus, transfer
of autoreactive K14 CD4+ T cells to syngeneic hosts can
prevent the engraftment of I-Ab-positive bone marrow and
cause acute GVHD.
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CGVHD can be induced in nonirradiated mice through the transfer of allogeneic CD4+ T cells recognizing different MHC class II loci (30). Disease manifestations mimic those of human systemic lupus erythematosus and MRL/Mp-lpr mice (31, 32). Animals develop evidence of Ag-independent B cell activation with lymphadenopathy, splenomegaly, hypergammaglobulinemia, and autoantibody production. Hypergammaglobulinemia results in immune complex deposition in the kidney with associated glomerulonephritis, proteinuria, and death (33).
To determine whether autoreactive K14 cells could mediate chronic GVHD, wild-type unirradiated male recipient B6 mice received a single i.v. injection of either 1 x 107 or 1 x 106 purified K14 CD4+ T cells. Control mice were injected with medium alone. Mice were maintained in a germfree barrier facility during the course of the experiment and were followed for evidence of disease, such as lethargy, weight loss, proteinuria, or death. Recipient animals were also bled intermittently to allow for Ab detection and quantification.
Over a period of 8 mo, no animal deaths were recorded. Likewise, there was neither weight loss, decreased food intake or lethargy, nor increased mortality in the experimental group vs the control group of B6 mice.
Eight weeks after initiation of the disease process, two mice receiving
107 K14 T cells and two control mice were sacrificed. Flow
cytometric examination of the spleen and lymph node revealed equivalent
numbers of lymphocytes in the experimental and control animals as well
as equivalent ratios of T cells to B cells and of CD4 to CD8 cells.
However, the CD4+ T cells in the treated animals had the
phenotype of memory cells with a large proportion of
CD62Ldull cells (Fig. 1B). B220+ B cells
in the treated animals had an increased level of MHC class II on their
surface, suggesting that they, too, had been activated (Fig. 1A). In parallel with this B cell activation, pathology
showed an increased number of germinal centers in lymph node and spleen
of the experimental animals (data not shown).
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C shows the level of total serum IgG that developed in
individual groups of mice over the course of the experiment. The mice
injected with either 107 or 106 K14
CD4+ T cells uniformly developed hypergammaglobulinemia and
maintained these levels over the course of the experiment. Indeed, 8 mo
after inoculation, total IgG in the treated groups was at least twice
that in the untreated controls (data not shown).
At 8 wk, the presence of anti-nuclear Abs was assayed by
immunofluorescence. No anti-nuclear Abs were detectable in either
B6 mice treated with medium alone or control unmanipulated animals,
even using undiluted serum. In contrast, all the B6 mice that had
received 107 K14 CD4+ T cells developed
anti-nuclear Abs, which were detectable by immunofluorescence at a
serum dilution of 1/40. A representative experiment is shown in Fig. 1D. The anti-nuclear Abs produced by the host B cells in
CGVHD include anti-chromatin and anti-DNA Abs (31). We
therefore measured the titers of anti-ssDNA Abs by ELISA in serum
from the K14
B6 mice. As shown in Fig. 1E, titers
of anti-ssDNA were consistently elevated in recipient mice at 8,
13, and 17 wk.
Despite the presence of autoantibody production and hypergammaglobulinemia, no recipient animal developed proteinuria, which is due to immune complex deposition in the kidney. Histologic examination of the kidneys of two animals that received 107 cells revealed no gross pathology (data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We previously observed that the Vß usage by peripheral
CD4+ T cells in K14 mice, in which no negative selection
was apparent, was similar to that in wild-type B6 mice (25). These data
suggest that the gross repertoire is formed by positive selection, with
minimal contribution of negative selection. In the present study we
further examined the subset of CD4+ T cells that is
autoreactive through the analysis of autoreactive K14 T hybrids.
Strikingly, more than half the hybrids examined reacted to both self
and allogeneic APC. Other investigators have also examined the
specificity of T cells selected in well-delineated environments.
Zerrahn et al. described a series of hybrids that reflected the
reactivity of TCRs before either positive or negative selection (34).
They found that approximately 5% of a panel of CD4-expressing hybrids
was MHC restricted. Within this subpopulation, the number of hybrids
reactive with more than one MHC haplotype was no greater than that
predicted by Poisson distribution. Ignatowicz et al. (35) examined the
frequency of self- and allo-reactive cells in a murine model in which
both positive and negative selection of T cells occurred on a single
peptide-MHC complex, Y-Ae. Two-thirds of the resultant hybrids
responded to syngeneic MHC. However, the majority of these were peptide
independent and responded to invariant chain-negative APC, suggesting
that limiting the number of MHC-peptide complexes skews the TCR
repertoire toward MHC framework determinants. A large percentage of the
self-reactive hybrids (
30%) was also allo reactive. Our previous
data in combination with these models show that positive selection
skews the resultant T cell repertoire toward both auto- and
allo-reactivity. The significant overlap between self-reactive and
allo-reactive clones in the K14 hybrids is similar to the frequencies
of self- and allo-reactivity observed in hybrids selected on a single
self peptide. Thus, either limiting the peptide population or
eliminating efficient negative selection skews the mature T cell
population toward self reactivity. The resultant allo-reactivity
follows from the self reactivity.
Single peptide-expressing mice (36) and DM-deficient mice, which express a very limited set of self peptides (37, 38), do not have an intact mature repertoire due to incomplete positive selection. We have not been able to demonstrate that the K14 mice have a complete repertoire responsive to a variety of Ags. In vivo Ag-specific responses are absent due to the lack of class II-expressing APC, and in vitro Ag-specific responses are obscured by the large self-reactive response (data not shown). However, allogeneic reactivity is believed to represent a polyclonal response to the diverse peptides presented by allogeneic APC (39). Thus, the broad spectrum of Vß usage, in addition to the reaction to allogeneic class II molecules, is an indirect indicator of T cell diversity.
Having confirmed that the K14-derived autoreactive cells are indeed polyclonal, we investigated their potential to mediate autoimmune disease in two distinct adoptive transfer models. The addition of 107 purified K14 CD4+ T cells to a T-depleted B6 bone marrow graft causes graft rejection and death in lethally irradiated B6 hosts. Additionally, K14 CD4+ T cells mediate chronic GVHD when administered to nonirradiated B6 hosts. The addition of 107 CD4+ T cells produces nonspecific B cell activation (and an increase in I-Ab expression) that results in hypergammaglobulinemia and the production of autoantibodies. Moreover, inoculation of unirradiated hosts with only 106 K14 CD4+ T cells, <5% of the number of T cells usually required to initiate GVHD, is sufficient to induce hypergammaglobulinemia, although specific titers of either anti-nuclear Abs or anti-DNA Abs were not detected. Previous studies have demonstrated that development of chronic GVHD requires cognate T-B cell interaction; recipient B cells are directly stimulated by allo-reactive donor T cells, breaking the B cell tolerance that is normally maintained by a self-tolerant T cell compartment (40). Here, nontolerant K14 CD4+ T cells are interacting with wild-type I-Ab-expressing B cells and acting as allo-reactive cells.
Despite the prolonged hypergammaglobulinemia, no host animal developed
proteinuria or histologically apparent renal disease during the course
of the experiment. It is possible that we have introduced an
insufficient number of self-reactive CD4+ T cells to induce
immune complex renal disease; in most experiments 108
splenocytes (containing significantly more allo-reactive T cells)
initiate the disease. It is also possible that activation of host T
cells is required to perpetuate the process and induce renal disease,
and that in the K14B6 system, host B6 T cells do not
recognize K14 CD4+ T cells (also B6 derived) as foreign and
are not activated. These experiments were performed in our
pathogen-free facility, and as in the case of other autoimmune
diseases, such as HLA-B27-mediated spondyloarthropathy (41, 42) and
experimental allergic encephalomyelitis (43), it is possible that a
nonspecific environmental antigenic challenge is required to act as an
adjuvant. Finally, the development of renal disease in K14B6
syngeneic GVHD may be critically dependent on the presence of female
sex hormones, as is true for other immunologically mediated renal
disease in mice (44, 45) and systemic lupus erythematosus in humans. We
are currently investigating the activities of both donor and host T
cells during the induction of CGVHD in male and female hosts to
investigate these possibilities.
The presence of both in vitro reactivity in MLR and CTL and in vivo reactivity, which causes GVHD, demonstrates that K14/I-Ab-expressing cortical thymic epithelial cells do not induce split tolerance as does medullary thymic epithelium. The production of tolerance by thymic epithelial tissues in isolation from any bone marrow-derived cells has been examined by grafting embryonic thymic rudiments before the influx of hemopoietic cells (46). Additionally, Hoffmann et al. have examined the results of ectopically expressing the MHC class I molecule, Kb, in thymic cortical and medullary epithelium (through thymic grafts) or isolated in thymic medullary epithelium (secondary to transgene expression) (17, 20). In both cases, in vitro proliferative or cytotoxic responses were accompanied by in vivo tolerance to skin grafts. Secondary examination of the thymic selection of a Kb-restricted transgenic TCR suggested that this split tolerance resulted from the selective deletion of developing thymocytes with a high affinity for self, leaving only low affinity cells with a decreased surface density of the TCR that were incapable of effecting an in vivo immune response without primary stimulation. However, CD4+ T cells derived from K14 mice maintain their in vivo reactivity, which implies that thymic cortical epithelium does not induce split tolerance.
In distinct transgenic systems two groups have used the human K14 promoter to examine the immunologic consequences of ectopically expressing the human papilloma virus tumor Ag, E7, in skin and thymic epithelium. These groups reported differing results. Melero and his colleagues could find no demonstrable immunologic effect of the expression of the transgene (47), perhaps due to undetectably low levels of the expressed transgene. In contrast, Frazer and his colleagues described a split tolerance in which T cell proliferative responses to the E7 Ag were enhanced, however, E7-specific CTL precursor frequency, in vitro CTL activity, and in vivo anti-tumor effects were markedly diminished (48). Additional experiments with mixed bone marrow/thymic chimeras showed that the loss of CTL activity was induced by human papilloma virus tumor Ag E7 expression in skin keratinocytes rather than in thymic epithelium (49). Thus, that system mirrors the one we have described in that transgenes expressed in the thymic cortex do not mediate negative selection.
K14 CD4+ T cells are autoreactive due to the absence of
negative selection. Other models of autoreactivity that are associated
with incomplete thymic selection have also been described. Bonomo and
her colleagues have demonstrated that neonatal mice thymectomized on
days 2–5 of life develop organ-specific autoimmunity (50).
Interestingly, CD4+ T cells purified from the lymph nodes
of affected mice proliferated in an MLR to syngeneic dendritic cells.
Similarly, administration of cyclosporin A after syngeneic bone marrow
transplantation in rats elicits syngeneic GVHD, which is T cell
dependent (51, 52). The autoimmune diseases in both systems are
prevented in the presence of adult or euthymic CD4+ T
cells, suggesting that either thymectomy or cyclosporin A blocks the
normal thymic development of a regulatory or suppressive population of
CD4+ T cells (53, 54). Why doesn’t the presence of
autoreactive cells that react in a syngeneic MLR lead to organ-specific
autoimmune disease in the K14B6 mice? It is likely that the
anti-self-immune response is modified by the presence of adult
regulatory T cells present in the host, similar to those described in
post-thymectomy and post-cyclosporin A models. This theory is currently
being tested by transfer of K14 CD4+ T cells into C57BL/6
nude mice.
In conclusion, our data show that positive selection by normal thymic cortical epithelial cells, unopposed by negative selection (interaction with any other class II-positive cell), produces polyclonal CD4+ T cells that have sufficient affinity to self Ags to induce autoimmune disease.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Terri M. Laufer, Division of Rheumatology, University of Pennsylvania, 753 BRBII 421 Curie Blvd., Philadelphia, PA 19104. E-mail address:
3 Current address: Department of Immunology, IMM25, Scripps Research Institute, 10550 North Torrey Pines Rd., La Jolla, CA 92037.
4 Abbreviations used in this paper: AGVHD, acute graft-versus-host disease; CGVHD, chronic graft-versus-host disease.
Received for publication October 21, 1998. Accepted for publication February 2, 1999.
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M. Capone, P. Romagnoli, F. Beermann, H. R. MacDonald, and J. P. M. van Meerwijk Dissociation of thymic positive and negative selection in transgenic mice expressing major histocompatibility complex class I molecules exclusively on thymic cortical epithelial cells Blood, March 1, 2001; 97(5): 1336 - 1342. [Abstract] [Full Text] [PDF]
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A. Gaszewska-Mastalarz, P. Muranski, B. Chmielowski, P. Kraj, and L. Ignatowicz Altered Selection of CD4+ T Cells by Class II MHC Bound with Dominant and Low Abundance Self-Peptides J. Immunol., December 1, 2000; 165(11): 6099 - 6106. [Abstract] [Full Text] [PDF]
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S. Winer, L. Gunaratnam, I. Astsatourov, R. K. Cheung, V. Kubiak, W. Karges, D. Hammond-McKibben, R. Gaedigk, D. Graziano, M. Trucco, et al. Peptide Dose, MHC Affinity, and Target Self-Antigen Expression Are Critical for Effective Immunotherapy of Nonobese Diabetic Mouse Prediabetes J. Immunol., October 1, 2000; 165(7): 4086 - 4094. [Abstract] [Full Text] [PDF]
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A. I. Caplan and J. E. Dennis Genetically Linked Scientists: The One-Two Punch For NFATp Knockout J. Exp. Med., January 3, 2000; 191(1): 1 - 4. [Full Text] [PDF]
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