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Department of Microbiology and Molecular Genetics, University of California, Los Angeles, CA 90095
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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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Experimental autoimmune encephalomyelitis
(EAE)3 is a prototypic CD4 T
cell-mediated autoimmune disease and is an instructive model for the
human demyelinating disease, multiple sclerosis, because it shares many
of its pathological and immune dysfunctions (4). It is characterized by
inflammation and demyelination in the central nervous system
accompanied by paralysis following immunization with myelin Ags, for
example, myelin basic protein (MBP). A majority of the MBP-primed
effector CD4 T cells that mediate EAE in H-2u mice
recognize the N-terminal peptide MBP Ac1-9/Ac1-20 and predominantly use
the TCR Vß8.2 gene segment (5, 6). The CD4 T cell lines and clones
that adoptively transfer EAE invariably secrete proinflammatory
cytokines, such as IFN-
and/or lymphotoxin (7, 8, 9, 10). However, T cells
with the same specificity producing Th2-like cytokines generally are
nonencephalitogenic and in some cases prevent EAE in a bystander
fashion (11, 12, 13). Similarly, in several experimental systems treatment
of mice either with Abs to neutralize Th1 cytokines or with
administration of Th2 cytokines have been shown to be protective from
disease. Furthermore, endogenous levels of IL-4/IL-10 appear to
correlate with the recovery from EAE (14). Although these observations
collectively suggest that myelin Ag-specific Th1 cells are
encephalitogenic and Th2 are not, recent experiments indicate that the
regulation and function of individual cytokines is more complex; for
example, T cells that express a transgenic TCR specific for MBP can
induce EAE in immunodeficient recipients after culture under either
Th1- or Th2-polarizing conditions (15). Furthermore, systemic treatment
with cytokines can have an unexpected outcome as a result of complex
effects on other lymphoid populations, including regulatory T cell
populations (see Discussion).
Generally, Ag-induced EAE is transitory or monophasic in B10.PL mice, and spontaneous recovery from disease is associated with the physiological induction/expansion of regulatory CD4 T cells that recognize a framework 3 region determinant within TCR Vß8.2 (peptide "B5", amino acids 76–101/Au, also referred to as the TCR Fr3 peptide) (16, 17, 18, 19). These regulatory CD4 T cells together with recruited CD8 T cells, specific for a different determinant within the TCR Vß8.2 chain, appear to be involved in recovery from Ag-induced EAE. Thus, inactivation or absence of either the regulatory CD4 or CD8 T cells results in increased severity of disease and poor or delayed recovery (19, 20, 21). Furthermore, vaccination with disease-related T cells or their TCRs has been demonstrated to prevent or ameliorate experimental autoimmune diseases (17, 18, 22, 23, 24, 25, 26, 27). These observations have led to clinical trials of TCR-based vaccination in humans (28, 29, 30, 31). Although in different experimental systems, TCR peptide-reactive regulatory T cells have been shown to control disease, their mechanism of action or the role of cytokines in this regulation is largely unknown. In an attempt to directly investigate the mechanism of regulation, we asked whether a type 1 or type 2 cytokine profile within the well-defined TCR peptide-specific regulatory CD4 population is required for the regulation of EAE. Furthermore, does the action of regulatory CD4 T cells result in influencing the cytokine profile of the MBP-reactive T cell population and its capacity to mediate disease?
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B10.PL and SJL/J mice were purchased from The Jackson Laboratory (Bar Harbor, ME). (SJL x B10.PL)F1 mice were bred under specific pathogen-free conditions in our own colony. Female mice were used at 8–16 wk of age and were maintained on standard laboratory diet and water ad libitum.
TCR peptides
Vß8.2 TCR peptides used were the same as reported previously (17): B1, amino acids 1–30L (TCR Fr1 peptide); B4, amino acids 61–90; B5, amino acids 76–101 (TCR Fr3 peptide).
Measurement of Ag-specific proliferative responses
Lymph nodes or spleens of mice were removed 10 or 30 days after s.c. immunization with peptides derived from the MBP or the Vß8.2 chain, and single cell suspensions were prepared. To monitor nasal priming of regulatory CD4 T cells, spleens were removed 5–7 days after nasal instillation with TCR peptides. Lymph node cells (4 x 105 cells per well) and splenocytes (8 x 105 cells per well) were cultured in 96-well microtiter plates in 200 µl of serum-free medium (HL-1, Ventrex, Portland, ME, or X-vivo 10, BioWhittaker, Walkersville, MD) supplemented with 2 mM glutamine; peptides were added at concentrations ranging from 0.1 to 7 µM final concentration. Proliferation was assayed by the addition of 1 µCi [3H]thymidine (International Chemical and Nuclear, Irvine, CA) for the last 18 h of a 5-day culture, and incorporation of label was measured by liquid scintillation counting.
Induction and clinical evaluation of EAE
Mice were immunized s.c. with 100 µg of guinea pig MBP or Ac1-9 emulsified in CFA; 0.15 µg pertussis toxin (List Biological, Campbell, CA) was injected in 200 µl saline i.v. 48 h later. Mice were observed daily for signs of EAE until 50–60 days after immunization. The average disease score for each group was calculated by averaging the maximum severity of all of the affected animals in the group. Disease severity was scored on a 5-point scale, as described earlier (17): 1, flaccid tail; 2, hind limb weakness; 3, hind limb paralysis; 4, whole body paralysis; 5, death.
Measurement of lymphokine secretion
Lymphokine secretion by established T cell clones was measured
in the supernatants using a standard sandwich ELISA technique, as
described earlier (32). For fresh cultures, mice were challenged with
the TCR Fr3 peptide, B5, emulsified in CFA or IFA. Ten days later, the
frequency of Ag-induced IFN-- or IL-4-producing T cells was
determined using the sensitive, single-cell ELISA spot assay, as
described earlier (32). Briefly, after culture of lymph node or splenic
cells with Ag for 48 h, live cells were recovered, washed, and
transferred by serial dilution (from 104 to 5 x
105 cells per well) to 96-well microtiter plates
(Millipore, Bedford, MA) that had been precoated with the
capturing mAbs (anti-IFN- or anti-IL-4) at 2 mg/ml. After
24 h, cells were removed, and spots were visualized using
biotinylated detecting mAbs and avidin D-peroxidase in
conjunction with 3-amino-9-ethylcarbazole (Sigma, St. Louis, MO)
substrate. Spots were counted under a dissecting microscope, and the
frequency of Ag-specific cells was determined from the difference
between number of spots seen with and without Ag. All capturing and
detecting Abs pairs were purchased from PharMingen (San Diego, CA).
Nasal instillation (NI)
Following anesthesia with halothane, mice were nasally instilled
with peptides in PBS in a total volume of 20 µl. The effectiveness of
NI-mediated deviation of TCR Fr3 peptide responses toward Th2 is
dependent upon the dose and age of mice used (Melo et al., manuscript
in preparation). NI with 5–10 µg of B5 in 11- to 15-wk-old mice
resulted in almost complete deviation to Th2. Under these conditions,
IL-4 secretion predominates with insignificant levels of IFN-.
However, NI with a similar dose of B5 in 4-wk-old mice resulted in
simultaneous secretion of significant levels of both IFN- and IL-4.
Accordingly, in one experiment, 4-wk-old mice appeared to be protected
from disease.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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First, we tested the cytokine secretion profile of two TCR Fr3
peptide-specific regulatory CD4 T cell clones (B5.1 and B5.2) capable
of inducing protection from MBP-induced EAE when adoptively transferred
into B10.PL mice (17). Interestingly, both of these clones secrete
large amounts of IFN-, as well as IL-2, IL-4, IL-5, and a borderline
but detectable amount of IL-10 (for example, clone B5.2 secreted
IFN-, 641-1383 pg/ml; IL-4, 74–125 pg/ml; IL-5, 52–63 pg/ml; IL-2,
14–25 U/ml; and IL-10, 35–47 U/ml). Fresh cultures of T cells
isolated from mice challenged with TCR peptide B5 also secreted IFN-
and IL-4. T cell clones as well as freshly cultured lines, specific for
TCR Fr3 peptide, did not produce detectable amounts of TGF-ß.
Therefore, TCR peptide-specific regulatory CD4 clones do not resemble
Th3 (11) or TR1 (33) cells, which exhibit heightened secretion of
TGF-ß or IL-10, respectively.
Priming of type 2 regulatory CD4 T cells exacerbates EAE
Anti-inflammatory type 2 cytokines, such as IL-4, IL-10, or
TGF-ß, have been shown to be involved in a bystander fashion in
control of pathogenic autoreactive T cells (1, 34). To determine
whether Th2 cytokine secretion by TCR peptide-specific CD4 T cells
could control EAE, we used a NI technique known to deviate responses in
a Th2 direction (35). As shown in Fig. 1
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NI of B10.PL mice with an appropriate level (5–10 µg) of TCR Fr3
peptide, B5, results in priming of regulatory T cells that
predominantly secrete IL-4 and very little IFN-. There was no
response to a control TCR Vß8.2 peptide (B1, amino acids 1–31,
referred to as TCR Fr1 peptide). Five days following NI with a control
Ag, such as HEL or another TCR Vß8.2 peptide (B4, amino acids
61–90), splenic cells did not show any proliferative response or
cytokine production in in vitro recall assays (data not shown).
Collectively, these data suggest that TCR Fr3 peptide-reactive T cells
can be readily activated upon nasal exposure. Having established
the nasal instillation conditions for Th2 priming of regulatory CD4 T
cells, groups of B10.PL or (SJL x B10.PL)F1 mice
(both of these strains behave almost identically in response to the TCR
peptide B5/Au, as well as in the anti-MBP
encephalitogenic response in our experiments) were nasally instilled
with the TCR Fr3 peptide, or as a control the TCR Fr1 peptide, PBS, or
another immunogenic HEL peptide, 30-53, and were s.c. challenged 5–7
days later with MBP Ac1-9/CFA followed by i.v. pertussis toxin to
induce EAE. A typical disease course in these mice is shown in Fig. 2, and a summary of five independent
experiments is presented in Table I. It
is clear that mice nasally instilled with the TCR Fr3 peptide contract
a distinctly more chronic and severe disease (mean disease score, 4.6)
than mice in control groups (mean disease score, 2.1). In the combined
TCR Fr3 peptide groups, 20 of 29 mice did not show the typical
monophasic disease course but became moribund or died from severe
paralysis. This disease profile is similar to that induced in the
absence of regulatory CD4 or CD8 T cells (19, 20, 21). In contrast, mice
nasally instilled with PBS, the TCR Fr1 peptide, or HEL 30-53 before
Ac1-9 challenge contracted milder, typical EAE with over 90% of the
mice showing spontaneous recovery (Table I). Notably, in the group
nasally instilled with the TCR Fr3 peptide B5, mice contract disease
about 3 days earlier than in the control group (see Table I).
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To determine whether NI per se was disruptive for regulation, Th1
priming via the mucosal route was attempted. The presence of IL-12
during an initial antigenic challenge has been shown to result in the
development of Th1 responses and enhanced secretion of IFN- by
differentiated Th1 cells (36). Therefore, in an attempt to reinstate
Th1 induction of regulatory T cells, mice were nasally instilled with
IL-12 along with the peptide. NI with the TCR Fr3 peptide (10 µg B5
per mouse) and IL-12 (0.2–0.3 µg per mouse) resulted in priming of
B5-reactive T cells secreting significant amounts of IFN-. Groups of
mice were nasally instilled with the TCR Fr3 peptide or the control TCR
Fr1 peptide in combination with IL-12 or IL-4 and were subsequently
challenged with Ac1-9/CFA/pertussis toxin to induce EAE. The data in
Table II clearly demonstrate that the
groups of mice nasally instilled with TCR Fr3 peptide and IL-12 were
significantly protected from Ag-induced EAE. In experiment 1, only 2 of
8 mice contracted mild disease, while in experiment 2, the severity of
disease was strongly down-modulated. In contrast, mice in other groups,
including those receiving IL-12 with the irrelevant TCR Fr1 peptide,
contracted typical EAE. These results suggest that Th1-like cytokine
secretion by regulatory TCR peptide-specific CD4 T cells is required
for efficient control of encephalitogenic MBP-reactive T cells.
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or IL-4.
Regulatory CD4 T cell lines derived from mice nasally instilled with B5
peptide plus IL-4 secreted more IL-4 than IFN-, whereas T cell lines
from mice nasally instilled with B5 peptide plus IL-12 secreted much
more IFN- than IL-4 following in vitro recall with the TCR peptide
(Table III). These lines were then
adoptively transferred into naive (SJL x B10.PL)F1
animals to examine their ability to protect recipients from subsequent
induction of EAE. As shown in Table III, only groups of mice receiving
type 1 regulatory CD4 T cell lines were significantly protected from
Ac1-9-induced EAE. In contrast, mice in groups immunized with PBS or
Th2-like regulatory T cell populations contracted typical EAE.
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Next, we determined how regulatory T cells influenced the MBP Ac1-9/Ac1-20-specific encephalitogenic T population. Our earlier experiments in B10.PL mice with adoptive transfer of cloned regulatory CD4 T cells, the administration of TCR Fr3 peptide, a recombinant single-chain TCR (scTCR) protein containing a Vß8.2 domain, or plasmid DNA encoding the Vß8.2 chain all indicate that the heterogeneous population of Vß8.2 T cells are neither deleted nor inactivated (17, 18, 37, 38, and V. Kumar, unpublished observations). Recently, we and others have shown that in vivo priming/expansion of B5-reactive T cells using the Vß8.2 scTCR protein or plasmid DNA-encoding TCR Vß8.2 results in Ag-specific immune deviation and significant protection from EAE (17, 32, 37–39, and V. Kumar, unpublished observations).
To directly address the fate of the MBP Ac1-20-specific effector T cell
population and the predominance of Th1- or Th2-like cells within it
following the induction of TCR peptide-reactive regulatory (type 1) vs
nonregulatory (type 2) CD4 T cells, groups of mice were nasally
instilled with TCR Fr3 peptide alone or together with IL-12 or IL-4 and
then s.c. challenged with MBP Ac1-20. Ten days later, the frequency of
Ac1-20-specific and TCR peptide-reactive T cells, secreting either
IFN- (type 1) or IL-4 (type 2), was determined using an ELISA-spot
assay. There were no significant differences in the proliferative
responses to Ac1-20 in the draining lymph node cells from mice in these
groups, and the responses ranged from 34,571 ± 4,806 to
46,641 ± 1,150. However, as shown in Fig. 3, the frequency of TCR Fr3
peptide-specific T cells secreting IFN- was much higher and the
frequency of cells secreting IL-4 was lower in mice nasally instilled
with the TCR Fr3 peptide and IL-12. The opposite was true for mice
nasally instilled either with the TCR Fr3 peptide alone or together
with IL-4. Most importantly, the frequency of Ac1-20-specific T cells
secreting IL-4 increased while those secreting IFN- decreased in
mice nasally instilled with TCR Fr3 peptide plus IL-12, indicative of
deviation toward a type 2 response among the Ac1-20-reactive effector T
cells. In contrast, the frequency of Ac1-20-reactive T cells secreting
IFN- was higher in mice nasally instilled with the TCR Fr3 peptide
alone or along with IL-4, in accord with the observed exacerbation of
pathogenicity.
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C, mice nasally instilled
with TCR Fr3 peptide plus IL-12 showed higher levels of anti-Ac1-20
Abs of the IgG1 isotype (Th2) and lower levels of Abs of the IgG2a
isotype (Th1). In comparison, the levels of anti-Ac1-20 Abs of the
IgG2a isotype were higher, and of the IgG1 isotype lower, in mice
nasally instilled with TCR Fr3 peptide alone or together with IL-4. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Earlier studies in two experimental autoimmune disease models, EAE and
collagen-induced arthritis (16, 25, 41), as well as findings described
here suggest that spontaneously primed TCR peptide-specific regulatory
T cells are crucially involved in controlling autoreactive T cells, and
that immune regulation is one of the important mechanisms for
maintaining peripheral tolerance to self-Ags. Furthermore, a functional
balance among Ag-specific T cells and regulatory T cells is crucial for
the maintenance of peripheral tolerance (42). Thus, under conditions of
dysregulation where regulatory CD4 T cells are forced to deviate in a
Th2 direction and are unable to control MBP-reactive T cells, mice not
only contract severe and chronic EAE but also develop disease earlier
than in control mice. The development of early, more severe and chronic
EAE, as well as the very poor recovery from chronic disease, indicates
that the induction of regulatory Th2 cells represents a condition of
physiological dysregulation. Therefore, it is likely that
physiologically primed/activated TCR Fr3 peptide-reactive T cells are
Th1-like, which mediate spontaneous recovery from a single episode of
EAE. Consistent with this idea, in preliminary experiments TCR peptide
B5-reactive T cells, in mice recovering from EAE, appear to be
predominantly Th1-like (V. Kumar, unpublished observations). Also,
B10.PL mice challenged with B5 in IFA or CFA secrete much more IFN-
than IL-4 (data not shown). Furthermore, our findings that regulatory T
cells are readily primed within 3–5 days either following NI or
following s.c. immunization with TCR Fr3 peptide suggest that
TCR-reactive T cells pre-exist in healthy animals. Consistent with
this, we have earlier suggested (16, 17) that TCR determinants could be
potentially displayed in the context of both class I and/or class II
molecules by professional APCs that are able to pick up TCR from
apoptotic T cells during normal turnover in the periphery.
In a number of systems, the mucosal route has been shown to be an important site for priming Ag-specific responses (43, 44). Our data further suggest that NI with appropriate cytokines can be used to deviate responses in a type 1 or type 2 direction. Thus, NI with rIL-12 concomitant with the Ag leads to priming of a predominantly Th1-like response, whereas NI in the presence of IL-4 primes a predominant Th2-like response. It is noteworthy that significant priming (both proliferative response and cytokine secretion) to TCR Fr3 peptide B5 occurs 5 days following a single NI with 10 µg of this peptide in the absence of any adjuvant. This clearly indicates the effectiveness of priming via the nasal route. Because under identical conditions a significant proliferative or cytokine response is not seen this early with other immunogenic TCR or HEL peptides, it appears that TCR peptide-reactive T cells represent an already activated or memory population, as suggested above.
Immune deviation of Ag-specific T cells at the population level may explain how TCR-based regulation directed to a single Vß-chain is able to control disease-inducing, MBP Ac1-9-specific T cells that use other TCR V-chains, for example Vß13 or Vß4 (45). Accordingly, such modulation of T cell responsiveness to the target antigenic determinant may provide a suppressive environment for responses to other antigenic determinants from the same protein, as well as from other myelin components that may arise as a result of determinant spreading during chronic demyelination (46). Consistent with this, it has been shown that the bulk T cell infiltrate disappears from the target organ and EAE is reversed in PL/J mice following deviation of Ag-specific T cells by an altered peptide ligand (12). Furthermore, it is not yet clear in this system whether physiologically primed T cells reactive to subdominant determinants of MBP detected in the spleen following determinant spreading are pathogenic or protective (47). Our recent observations suggest that priming of at least some of the T cells reactive to a subdominant determinant region (amino acids 121–150) of MBP results in significant protection from Ac1-9-induced EAE (V. Kumar et al., unpublished observations).
It is not yet clear how the action of type 1 regulatory T cells results
in the eventual dominance by the type 2-deviated population of CD4
effectors. Because TCR Fr3-reactive regulatory CD4 T cells cannot
recognize MBP-reactive effectors directly, it is possible that
secretion of type 1 cytokines indirectly influences encephalitogenicity
of effector CD4 T cells: inflammatory cytokines secreted by regulatory
CD4 T cells are required for efficient recruitment/activation of
regulatory CD8 T cells, either directly by interaction with CD8
cytotoxic effectors or via up-regulation of costimulatory molecules on
APCs to optimize induction of this CD8 population (16, 17, 18). Regulatory
CD8 T cells may induce apoptosis or anergy of the initially, rapidly
expanding, high-avidity, MBP-specific Vß8.2 Th1 cell population
(48, 49, 50). This would enable a relatively slower reacting compartment of
low-avidity, MBP-specific type 2 cells (which may or may not express
Vß8.2) to expand in the absence of cross-regulatory IFN- secreting
cells, resulting in immune deviation (37). We are currently
investigating these possibilities. Furthermore, which specific type 1
cytokines are involved in regulation by TCR-peptide-specific CD4 T
cells remains to be investigated.
These data are consistent with recent observations in several
experimental autoimmune disease systems where removal of a Th1 cytokine
such as IFN- seems to exacerbate disease, or treatment at a
particular time with Th1-inducing cytokines like IL-12, was shown to
protect rather than potentiate autoimmune disease (51, 52, 53, 54, 55).
Accordingly, systemic treatment of autoimmune disease with Th1- or
Th2-promoting cytokines can have unexpected, deleterious effects as has
been noted in some cases (51, 52, 53, 54, 55, 56). It is evident that the existence of
a distinct regulatory CD4 population in the correct functional
(proinflammatory) state plays a crucial and dominant role in the
eventual deviation of the potentially pathogenic autoreactive T cell
population in a type 2 direction, thus providing protection from
autoimmune disease. Consistent with this view, a number of
TCR-peptide-reactive T cells in humans have also recently been shown to
produce IFN- (31).
Although it may seem counterintuitive, type 1 regulatory CD4 T cells apparently are a prerequisite for the efficient control of disease-causing myelin-Ag-specific T cells. In the inflammatory milieu arising from the activation of Vß8.2 Ac1-9-reactive Th1 cells, the situation is established for the eventual down-regulation and deviation of this effector population. We have demonstrated that the TCR Fr3 peptide-reactive T cells are predominantly of the type 1 phenotype following priming of B10.PL mice with recombinant single-chain Vß8.2 TCR or plasmid DNA-encoding Vß8.2, which prevent EAE (37, 38, and V. Kumar, unpublished observations). A full understanding of the specific cytokine requirements of TCR peptide-specific regulatory CD4 T cells and their mechanism of action in regulation is crucial in exploiting therapeutic intervention of autoimmune disease in humans.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Vipin Kumar, Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, 10355 Science Center Drive, San Diego, CA 92121-1489; E-mail address:
3 Abbreviations used in this paper: EAE, experimental autoimmune encephalomyelitis; MBP, myelin basic protein; NI, nasal instillation.
Received for publication June 10, 1998. Accepted for publication August 26, 1998.
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References |
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 M. W. Cunningham Cardiac Myosin and the TH1/TH2 Paradigm in Autoimmune Myocarditis Am. J. Pathol., July 1, 2001; 159(1): 5 - 12. [Full Text] [PDF]
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V. Kumar, J. Maglione, J. Thatte, B. Pederson, E. Sercarz, and E. S. Ward Induction of a type 1 regulatory CD4 T cell response following V{beta}8.2 DNA vaccination results in immune deviation and protection from experimental autoimmune encephalomyelitis Int. Immunol., June 1, 2001; 13(6): 835 - 841. [Abstract] [Full Text] [PDF]
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A. Quinn, B. McInerney, E. P. Reich, O. Kim, K. P. Jensen, and E. E. Sercarz Regulatory and Effector CD4 T Cells in Nonobese Diabetic Mice Recognize Overlapping Determinants on Glutamic Acid Decarboxylase and Use Distinct V{{beta}} Genes J. Immunol., March 1, 2001; 166(5): 2982 - 2991. [Abstract] [Full Text] [PDF]
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T.-J. Huang, P. A. MacAry, P. Eynott, A. Moussavi, K. C. Daniel, P. W. Askenase, D. M. Kemeny, and K. F. Chung Allergen-Specific Th1 Cells Counteract Efferent Th2 Cell-Dependent Bronchial Hyperresponsiveness and Eosinophilic Inflammation Partly Via IFN-{{gamma}} J. Immunol., January 1, 2001; 166(1): 207 - 217. [Abstract] [Full Text] [PDF]
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E. A. E. van Tienhoven, C. P. M. Broeren, A. Noordzij, J. P. A. Wagenaar, W. van Eden, and M. H. M. Wauben Nasal application of a naturally processed and presented T cell epitope derived from TCR AV11 protects against adjuvant arthritis Int. Immunol., December 1, 2000; 12(12): 1715 - 1721. [Abstract] [Full Text] [PDF]
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G. L. Costa, J. M. Benson, C. M. Seroogy, P. Achacoso, C. G. Fathman, and G. P. Nolan Targeting Rare Populations of Murine Antigen-Specific T Lymphocytes by Retroviral Transduction for Potential Application in Gene Therapy for Autoimmune Disease J. Immunol., April 1, 2000; 164(7): 3581 - 3590. [Abstract] [Full Text] [PDF]
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H. Suzuki, Y. W. Zhou, M. Kato, T. W. Mak, and I. Nakashima Normal Regulatory {alpha}/{beta} T Cells Effectively Eliminate Abnormally Activated T Cells Lacking the Interleukin 2 Receptor {beta} In Vivo J. Exp. Med., December 6, 1999; 190(11): 1561 - 1572. [Abstract] [Full Text] [PDF]
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A. Lobell, R. Weissert, S. Eltayeb, C. Svanholm, T. Olsson, and H. Wigzell Presence of CpG DNA and the Local Cytokine Milieu Determine the Efficacy of Suppressive DNA Vaccination in Experimental Autoimmune Encephalomyelitis J. Immunol., November 1, 1999; 163(9): 4754 - 4762. [Abstract] [Full Text] [PDF]
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M. Falcone, B. Yeung, L. Tucker, E. Rodriguez, and N. Sarvetnick A Defect in Interleukin 12–induced Activation and Interferon {gamma} Secretion of Peripheral Natural Killer T Cells in Nonobese Diabetic Mice Suggests New Pathogenic Mechanisms for Insulin-dependent Diabetes Mellitus J. Exp. Med., October 4, 1999; 190(7): 963 - 972. [Abstract] [Full Text] [PDF]
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