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Departments of
* Ophthalmology and Visual Sciences and
Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110; and
Division of Cellular Immunology, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121
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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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It is thought that tolerance induced by haptenated spleen cells is related to the route of administration, the dose of Ag, and/or the availability of costimulators. The route is clearly important, as the same dose of these Ags given i.v. induces tolerance but the same dose given s.c. induces immunity (3). This suggests that the presence or absence of costimulation is unlikely to be the only determining factor. Another critical factor seems to be the lymphoid organ that takes up the Ag. The spleen has been shown to be of critical importance, as it is more difficult to tolerize splenectomized animals (1, 4). Still another observation is that the tolerance can be split, i.e., Ab and CTL responses can be unaffected, while only delayed-type hypersensitivity responses are tolerized (7).
The lpr and gld mutations affecting Fas (CD95) and its ligand (Fas ligand (FasL),4 CD95 ligand), respectively, produce a lymphadenopathy in mice that is associated with acceleration of autoimmune responses (8). The finding that Fas/FasL interactions are required for efficient activation-induced apoptosis in T cells in vitro (9), and for peripheral T cell deletion in vivo (10), suggests that defects in apoptosis contribute to lymphoid cell accumulation and autoimmune dysfunction. These mutations also affect tolerance induction in some systems (11, 12, 13), thereby implicating Fas/FasL interactions in other forms of tolerance.
Recently, the uptake of apoptotic cells by dendritic cells was shown to direct associated Ags to the class I MHC presentation pathway allowing cross-priming of CD8+ T cells (14, 15, 16, 17). The uptake of apoptotic cells has been suggested to prevent maturation of dendritic cells to an immunostimulatory state, as well as to promote tolerance induction (18). In this work we relate Fas-mediated apoptosis of haptenated splenocytes, uptake by dendritic cells, and cross-priming of CD8+ T cells to the induction of unresponsiveness in mice. Furthermore, we show that the transfer of such unresponsiveness requires both CD4+ and CD8+ T cells, and that the former can be replaced by stimulatory anti-CD40 Ab. These results are discussed in terms of a model of adult unresponsiveness mediated by activated T cells, cross-primed to Ags on apoptotic cells.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C57BL/6 (B6) mice were purchased from the National Cancer
Institute (Frederick, MD). B6-gld and B6-lpr we
bred in our own facility from strains originally obtained from The
Jackson Laboratory (Bar Harbor, ME).
2-microglobulin (2m)
knockout mice were purchased from The Jackson Laboratory.
Reagents
2,4,6-Trinitro-1-chlorobenzene (TNCB) was purchased from Eastern
Chemical (Smithtown, NY). 2,4,6-Trinitrobenzene sulfonic acid (TNBS)
was purchased from Sigma-Aldrich (St. Louis, MO). Anti-CD11c-FITC and
anti-CD8
-PE were purchased from BD PharMingen (San Diego, CA).
Anti-CD8 (clone 53.6.7) and anti-CD4 (clone RL574) supernatants
used for cytotoxic depletion were obtained from the laboratory of Dr.
P. M. Stuart (Washington University, St. Louis, MO). Pooled rabbit
complement was purchased from Pel-Freez Clinical Systems (Brown Deer,
WI). ZVAD-fmk was obtained from Calbiochem (San Diego, CA). Anti-CD-40
(FGK45) and anti-CD40 ligand (CD40L; MR-1) Abs have been described
(19). Mice received a single injection of 300 µg FGK45
or 250 µg MR-1 as indicated.
TNP coupling of spleen cells
Spleen cells were isolated from spleen and coupled with trinitrophenyl (TNP) as previously described (11). Briefly, 108 cells were incubated in 0.5 ml HBSS and 0.5 ml 10 mM TNBS for 7–10 min at room temperature. After incubation, cells were washed three times with HBSS before use. TNP-coupled splenocytes (TNP-spl) were irradiated unless otherwise indicated.
Induction of i.v. tolerance
TNP-coupled spleen cells were irradiated (3000 rad) or left untreated and injected i.v. via the retro-orbital plexus. Mice were immunized 48 h later with 0.05 ml of 1% TNCB in acetone/olive oil (3/1) applied to shaved abdominal skin. Five days later mice were challenged with 0.033 ml 10 mM TNBS in PBS in the right footpad and 0.033 ml PBS in the left footpad. Values are expressed in micrometers (± SE) and represent the difference between the right footpad (Ag challenge) and the left footpad (PBS challenge). Background values represent the difference between the challenged and unchallenged footpad in unimmunized mice.
Isolation of splenic adherent cells for cell sorting
Spleens were removed and ground between the frosted ends of
glass slides. All tissue was collected and centrifuged for 10 min at
200 x g. Pellets were resuspended in complete RPMI
(RPMI 1640 supplemented with 10% FCS,
L-glutamine, sodium pyruvate,
penicillin/streptomycin/fungizone, HEPES, and 2 x
10-5 M 2-ME), along with 50 µg/ml collagenase
type 2 (Worthington Biochemical, Lakewood, NJ), and 0.02 µg/ml DNase
I (2 ml/spleen; Roche, Indianapolis IN). This mixture was placed in a
37°C/5% CO2 incubator on a rotator for 45 min.
EDTA (10 mM) was then added and the cell suspension was incubated for
an additional 10 min. The cell suspension was then washed three times
with HBSS and RBCs were lysed with a Tris-lysing buffer. Cells were
then placed in 100 x 20 mm tissue culture dishes (Corning,
Corning NY) at an equivalent concentration of one spleen
(108 cells) per dish in 5 ml of complete RPMI and
placed in a 37°C/5% CO2 incubator for 1.5
h. Dishes are swirled twice at 30-min intervals. Nonadherent cells were
collected, and the plate was washed with
Ca2+/Mg2+-free HBSS and
placed at 4°C for 30 min. Adherent cells were then harvested with a
cell scraper. Following washing with
Ca2+/Mg2+-free HBSS, cells
were stained with anti-CD8-PE (BD PharMingen) and
anti-CD11c-FITC (BD PharMingen) on ice for 30 min. Cells were then
washed two times with
Ca2+/Mg2+-free HBSS and
subjected to cell sorting with FACSVantage (Beckman, San Jose, CA).
Cell sorting was performed based upon staining for CD8-PE and
CD11c-FITC, resulting in four populations:
CD8-CD11c-,
CD8+CD11c-,
CD8+CD11c+, and
CD8-CD11c+. The
adherent cell fraction was consistently 2–3% of the total cells
isolated from the spleen. The four sorted populations were injected
i.v. into mice at the equivalence of one spleen per recipient.
Adoptive transfer of adherent cells fed apoptotic cells
Spleen cell suspensions were prepared as described above. Following collagenase/DNase treatment, 5 x 106 cells in 1 ml of complete RPMI were placed in the wells of a 24-well plate and incubated for 2 h at 37°C in a 5% CO2 incubator. Wells were then washed three times with HBSS to remove nonadherent cells and 1 x 106 irradiated TNP-spl were added per well in complete RPMI. Following 2 additional hours of incubation at 37°C, wells were washed three times with Ca2+/Mg2+-free HBSS and the plates were placed at 4°C for 30 min. Cells were dislodged with a cell scraper, washed again in HBSS, and counted, and 1 x 104 viable cells were transferred to naive mice. Mice were immunized with TNCB as described above.
Adoptive transfer of splenic adherent and nonadherent cells
Twenty-four hours following i.v. injection of irradiated TNP-spl, spleen cell suspensions from tolerized mice were prepared as described above. Following collagenase/DNase treatment, cells were resuspended in complete RPMI and placed in 100 x 20 mm tissue culture dishes (Corning) at an equivalent concentration of one spleen (108 cells) per dish in 5 ml of complete RPMI. Dishes were incubated for 2 h at 37°C in a 5% CO2 incubator. The nonadherent cells were removed, the dishes were washed three times with HBSS, and 1 x 106 irradiated TNP-spl were added per well in complete RPMI. Following 2 additional h of incubation at 37°C, wells were washed three times with Ca2+/Mg2+-free HBSS and the plates were placed at 4°C for 30 min. Cells were dislodged with a cell scraper and washed in HBSS. Naive recipient mice received the equivalent of one spleen’s worth of adherent cells, nonadherent cells, or unseparated spleen cells. Mice were immunized with TNCB as described above.
Isolation of T cells
T cells were isolated from spleen cells suspension as previously described (20, 21). Briefly, 5-ml econocolumns (Bio-Rad, Richmond, CA) were filled with glass beads (mean diameter: 200 µm) coated with normal mouse Ig. The columns were washed three times with HBSS followed by the addition of a 1/6 dilution of rabbit anti-mouse Ig. After a 1-h incubation, the column was washed three times with HBSS. Spleen cells (108/2.5 ml beads) were added to the column with a flow rate of one drop per 6–10 s. Cells were collected as they emerged from the column. Yields were typically 25–30% of the applied cells that consisted of 95–98% CD3+ cells. CD4+ and CD8+ T cells were obtained by negative selection. Purified T cells were treated with anti-CD4 (clone RL574) or anti-CD8 (clone 53.6.7) plus rabbit complement (1/16). Cells were transferred to recipient mice at equivalence, where each recipient mouse received the equivalence of one spleen’s worth of the appropriate cell population.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A, induction of a vigorous
contact hypersensitive response in C57BL/6 (B6) mice was blocked by
prior i.v. injection of B6 TNP-Spl.
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A shows
that i.v. injection of TNP-spl from wild-type B6 mice induced
unresponsiveness in both B6 and Fas-defective B6-lpr
recipient mice. In contrast, unresponsiveness was not induced with
TNP-coupled lpr splenocytes, or when TNP-spl from wild-type
mice were injected into FasL-defective gld mice. These
results show that for unresponsiveness to occur in this system Fas must
be present on the TNP-spl and functional FasL must be available in the
recipient.
One likely role for Fas/FasL interactions may be to induce apoptosis in
the injected cells. To examine this possibility, nontolerogenic
Fas-defective lpr spleen cells were coupled with TNP and
then irradiated to induce apoptosis. Irradiation of either wild-type
(Fig. 1B) or lpr (Fig. 1C) TNP-spl
increased the potency of these cells for induction of tolerance. In
contrast, TNP-spl fixed with paraformaldehyde (nonapoptotic) induced
tolerance only at very high doses (Fig. 1B).
Apoptosis proceeds via the activation and function of a number of
cysteine proteases, called caspases (22). Therefore, we
examined the effect of the pan-caspase inhibitor zVAD-fmk on tolerance
induced by irradiated TNP-spl. As shown in Fig. 1D, zVAD-fmk
treatment of irradiated TNP-spl completely prevented the induction of
tolerance by these cells. These results suggest that the activation of
caspases in TNP-spl was required for the induction of tolerance in this
system.
One role for caspase activation during apoptosis is the generation of
cell surface signals that promote phagocytosis of the dying cell
(22). Because the recipient spleen is important for
tolerance induction by haptenated cells (1, 4), we
examined this organ for phagocytic APCs that might transduce the
tolerogenic signal by engulfment of apoptotic cells. As shown in Fig. 2A, splenic adherent cells
obtained from mice injected 24 h earlier with TNP-spl transduce
tolerance when injected into naive mice, whereas the splenic
nonadherent cells did not. We further analyzed the adherent cell
population by examining expression of CD8 and CD11c, two markers
that identify cells capable of cross-presenting Ags. Cytotoxic
depletion of CD8+ cells from the adherent
population with Ab and complement eliminated the ability of these cells
to transfer tolerance (Fig. 2B). To more precisely identify
the splenic adherent cell population that transduced the tolerogenic
signal, splenic adherent cells obtained from mice injected 24 h
earlier with irradiated TNP-spl were sorted into four populations based
on CD8 and CD11c staining (Fig. 3A). Analysis of these
populations by adoptive transfer revealed that only the
CD8+CD11c+ (R3) cell
population transduced the tolerogenic signal (Fig. 3B). This
is despite the fact that these cells comprise 2–3% of the splenic
adherent population (Fig. 3A). Further analysis revealed
that only 25% of these
CD8+CD11c+ (or
0.5–0.075% of the total adherent cells) could be shown to have
accumulated labeled apoptotic cells (data not shown). This is
consistent with a recent report on the potency of these resident spleen
cells for inducing biological activity (23).
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highCD11c+ dendritic
cell subset is responsible for cross-priming. This cell population
comprises the lymphoid-derived subset of splenic APCs and is capable of
moving extracellular Ags into the intracellular class I MHC
presentation pathway (23). Data in Fig. 2 demonstrate that
the injected apoptotic cells enter the splenic adherent cell fraction
for transduction of the tolerogenic signal. Therefore, we examined the
possible role of class I-mediated cross-priming in this system by
culturing splenic adherent cells obtained from uninjected mice with
irradiated TNP-spl. Fig. 4 shows that
adherent cells from wild-type mice effectively transferred tolerance,
whereas adherent cells from animals lacking class I MHC expression
(2m deficient) did not. This requirement for
class I MHC and a role for
CD8highCD11c+ cells are
suggestive of a role for cross-priming of the phagocytosed hapten in
tolerance induction in this system.
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A, administration of an
anti-CD40 agonist Ab converted the tolerogenic TNP-spl to an
immunogenic signal. In contrast, blocking CD40/CD40L interactions with
an antagonistic anti-CD40L Ab had no effect on the ability of
TNP-spl to induce tolerance (Fig. 5B).
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shows that T cells
from animals injected with TNP-spl 7 days earlier transferred
unresponsiveness to naive mice, and this effect required both
CD4+ and CD8+ T cells. The
activation of a CD8+ T cell population is
consistent with the requirement for class I MHC and adherent cells
capable of cross-priming as observed in Figs. 2 and 3. In other
systems, the requirement for CD4+ Th cells in the
activation of CD8+ effector cells can be bypassed
by activation of CD40 on dendritic cells (19). As shown in
Fig. 6, the requirement for a CD4+ T cell in the
transfer of tolerance was overcome when an agonistic anti-CD40 Ab
was also injected with the CD8+ T cells.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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+CD11c+
splenic dendritic cells, which cross-prime CD8+ T
cells via presentation of haptenated peptides on class I MHC. The
CD8+ T cells regulate the immune response with
CD40/CD40L-mediated help from CD4+ T cells. Our
results are also consistent with the idea that immature dendritic cells
are responsible for transducing the tolerogenic signal, because
injection of a maturation signal in the form of anti-CD40 Ab
induces immunity. A recent report showing that that immature dendritic
cells tolerize recipients and induce regulatory T cells in humans
(14) also supports this idea.
Recent studies have suggested that exogenous Ags are presented in
association with class I molecules on dendritic cells to effector
CD8+ T cells (23). These cells were
identified as
CD8highCD11chigh
lymphoid-derived cells residing in the periarteriolar lymphatic
sheaths. Another population of splenic dendritic cells that is myeloid
derived (CD8-) resides in the marginal zones
(25) and does not appear to be involved in CD8 T cell
priming. It is interesting that the same cells
(CD8highCD11chigh) that
cross-prime CTLs also cross-prime regulatory T cells. This dendritic
cell population is extremely effective in transducing a tolerogenic
signal. Only 
1% of spleen cells are adherent by our method and the
CD8+CD11c+ cells
comprise 2–3% of this population. Therefore, only 0.002–0.003%
of the cells in the spleen cells appear to be responsible for the
observed effects. This is similar to the recent findings of den Haan et
al. (23), who found only a small percentage of cells
isolated from the spleen contained Ag for cross-priming of
CTLs.
Fundamentally different roles for CD40 stimulation were seen when we examined the induction of tolerance and the transfer of the CD8+ T cells from the tolerant mice. Whereas combination of CD40 activation with tolerogen yielded immunity, activation of CD40 was required for the inhibitory effect of the CD8+ regulatory T cells. Although these results may seem paradoxical, in a broader context they may make intuitive sense. Apoptosis occurs in normal tissue turnover and homeostasis, and we would expect that Ag associated with these apoptotic cells is tolerogenic. However, if apoptosis occurs during infection, additional signals that are present can activate the dendritic cells and immunity ensues. This was mimicked in our system by agonistic anti-CD40 Ab. However, if tolerance to the Ags has been established by prior exposure, subsequent contact results in activation of regulatory CD8+ T cells that prevent induction of potentially dangerous immune responses. This is now enhanced by the presence of the CD40 signal on the dendritic cells that activate the CD8+ T cells, via either activated CD4+ T cells or agonistic anti-CD40 Ab. Transduction of tolerogenic signals between regulatory T cells by dendritic cells was reported a number of years ago (26); therefore, it is possible that this represents the activation of the dendritic cell to present Ag to the regulatory CD8+ T cells.
Cognate help between CD4+ helper cells and CD8+ CTLs activated by cross-priming has been shown to occur via CD40L stimulation of dendritic cells (27), and this appears to be the role of the CD4+ T cell in the present system. Whether the CD4+ T cells have a particular cytokine profile, e.g., Th1 or Th2, is not known. However, in a similar system where CD4+ cells and CD8+ T cells cooperate to mediate tolerance, the CD4 cells are the Th2-like and result from the differentiation Ag presentation in the presence of apoptotic cells (28). We are currently performing studies to characterize the role of CD4+ T cell in the present system.
The mechanism of action of the CD8+ regulatory
cells is not known. One possibility is that these are Tc2-like cells,
producing inhibitory cytokines in response to antigenic stimulation
(29). To address this possibility we have tested
CD8+ cells from tolerized mice for candidate
cytokines by ELISA and intracellular cytokine staining. These tests
have not shown a discernable pattern for the production for IL-10,
TGF-, or IL-4 that could account for the observed effects. Even Ag
restimulation in vitro failed to produce detectable differences between
tolerized and nontolerized animals (data not shown). Alternatively, the
regulatory CD8+ T cells may be cytotoxic cells
that effectively destroy APCs bearing the appropriate ligand. To test
this we examined tolerance induction in perforin knockout mice
(30). We found that these mice were easily tolerized by
irradiated TNP-spl and contain regulatory CD8+ T
cells (data not shown). These data, coupled with our results showing
that FasL-defective gld mice are tolerized by irradiated
TNP-spl (Fig. 1A), suggest that cytotoxicity mediated by
perforin and/or FasL is not involved. Therefore, while
CD8+ T cells appear to be important in tolerance
induced by TNP-spl, the mechanism whereby these mediate their effects
remain elusive.
Tolerance induced by cross-priming of apoptotic cells has been
described for CD8+ CTLs (31). In
this situation, tolerance is defined as unresponsiveness in the
CD8+ population. Our data show the CD8s obtained
from cross-priming are regulatory cells. In either case, it is unclear
how the particular cross-priming conditions preferentially stimulate
these cells rather than mediate immunity. Apoptotic cells externalize
phosphatidylserine, and this activates a phosphatidylserine receptor
present on dendritic cells, macrophages, and other cells
(32), inducing the production of anti-inflammatory
cytokines such as TGF- (33). Apoptotic cells are also
known to produce immunoregulatory cytokines before death (28, 34). It is possible that this helps to promote the induction of
the regulatory T cells we have observed.
A connection between apoptotic cells and the induction of tolerance has been observed in other situations. Systemic immune deviation elicited following Ag presentation via an immune-privileged site was recently shown to require Fas/FasL-mediated apoptosis, engulfment of apoptotic cells by APCs, and presentation to T cells (11, 28). Similarly, the induction of tolerance by hapten sensitization through UV-exposed skin involves the induction of CD8+ regulatory T cells, and this requires Fas-FasL interactions in the animal (12, 35). These systems resemble the phenomena we have studied here and may involve similar mechanisms.
Conditions that result in the apoptosis of activated T cells can promote tolerance for graft rejection (36, 37), and expression of antiapoptotic Bcl-xL in the T cells prevents this nonresponsiveness (36). This may be related to the phenomenon we have described in this work, provided Ags from the graft are somehow associated with the apoptotic T cells. In support of this idea, it was recently shown that T cells can take up, internalize, and re-present peptides associated with MHC-peptide complexes on dendritic cells (38).
Our results not only extend current paradigms on the role of apoptosis, dendritic cells, and regulatory T cells in immune tolerance, but they also provide a mechanism for one of the most studied, but least understood, modes of inducing Ag-specific unresponsiveness. Further studies into signals that induce immunity or tolerance, as well as insights into the mechanism of maintaining the tolerance state, may help solve some of the more perplexing questions in autoimmunity and transplantation tolerance.
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Footnotes |
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2 Current address: Department of Urology, University of Iowa, Iowa City, IA 52242.
3 Address correspondence and reprint requests to Dr. Thomas A. Ferguson, Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, 660 South Euclid Street, Box 8096, St. Louis, MO 63110. E-mail address: Ferguson{at}vision.wustl.edu
4 Abbreviations used in this paper: FasL, Fas ligand; CD40L, CD40 ligand; TNP, trinitrophenyl; TNP-spl, TNP-coupled splenocyte; 2m, 2-microglobulin; TNCB, 2,4,6-trinitro-1-chlorobenzene; TNBS, 2,4,6-trinitrobenzene sulfonic acid.
Received for publication January 24, 2002. Accepted for publication April 3, 2002.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, PGE2, and PAF. J. Clin. Invest. 101:890.[Medline]
released by apoptotic T cells contributes to an immunosuppressive milieu. Immunity 14:715.[Medline]
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E. L. Turnbull, U. Yrlid, C. D. Jenkins, and G. G. MacPherson Intestinal Dendritic Cell Subsets: Differential Effects of Systemic TLR4 Stimulation on Migratory Fate and Activation In Vivo J. Immunol., February 1, 2005; 174(3): 1374 - 1384. [Abstract] [Full Text] [PDF]
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P. R. Hoffmann, J. A. Kench, A. Vondracek, E. Kruk, D. L. Daleke, M. Jordan, P. Marrack, P. M. Henson, and V. A. Fadok Interaction between Phosphatidylserine and the Phosphatidylserine Receptor Inhibits Immune Responses In Vivo J. Immunol., February 1, 2005; 174(3): 1393 - 1404. [Abstract] [Full Text] [PDF]
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A. Bondanza, V. S. Zimmermann, P. Rovere-Querini, J. Turnay, I. E. Dumitriu, C. M. Stach, R. E. Voll, U. S. Gaipl, W. Bertling, E. Poschl, et al. Inhibition of Phosphatidylserine Recognition Heightens the Immunogenicity of Irradiated Lymphoma Cells In Vivo J. Exp. Med., November 1, 2004; 200(9): 1157 - 1165. [Abstract] [Full Text] [PDF]
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M. Epardaud, M. Bonneau, F. Payot, C. Cordier, J. Megret, C. Howard, and I. Schwartz-Cornil Enrichment for a CD26hi SIRP- subset in lymph dendritic cells from the upper aero-digestive tract J. Leukoc. Biol., September 1, 2004; 76(3): 553 - 561. [Abstract] [Full Text] [PDF]
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R. Barreiro, G. Luker, J. Herndon, and T. A. Ferguson Termination of Antigen-Specific Immunity by CD95 Ligand (Fas Ligand) and IL-10 J. Immunol., August 1, 2004; 173(3): 1519 - 1525. [Abstract] [Full Text] [PDF]
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 P. M. Stuart, B. Summers, J. E. Morris, L. A. Morrison, and D. A. Leib CD8+ T cells control corneal disease following ocular infection with herpes simplex virus type 1 J. Gen. Virol., July 1, 2004; 85(7): 2055 - 2063. [Abstract] [Full Text] [PDF]
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M. D. Rosenblum, E. Olasz, J. E. Woodliff, B. D. Johnson, M. C. Konkol, K. A. Gerber, R. J. Orentas, G. Sandford, and R. L. Truitt CD200 is a novel p53-target gene involved in apoptosis-associated immune tolerance Blood, April 1, 2004; 103(7): 2691 - 2698. [Abstract] [Full Text] [PDF]
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V. S. Zimmermann, A. Bondanza, A. Monno, P. Rovere-Querini, A. Corti, and A. A. Manfredi TNF-{alpha} Coupled to Membrane of Apoptotic Cells Favors the Cross-Priming to Melanoma Antigens J. Immunol., February 15, 2004; 172(4): 2643 - 2650. [Abstract] [Full Text] [PDF]
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B. L. Colvin, A. E. Morelli, A. J. Logar, A. H. Lau, and A. W. Thomson Comparative evaluation of CC chemokine-induced migration of murine CD8{alpha}+ and CD8{alpha}- dendritic cells and their in vivo trafficking J. Leukoc. Biol., February 1, 2004; 75(2): 275 - 285. [Abstract] [Full Text] [PDF]
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A. B. Stavitsky Regulation of Granulomatous Inflammation in Experimental Models of Schistosomiasis Infect. Immun., January 1, 2004; 72(1): 1 - 12. [Full Text] [PDF]
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J. C. Zimring, S. B. Levery, B. Kniep, L. M. Kapp, M. Fuller, and J. A. Kapp CD75s is a marker of murine CD8+ suppressor T cells Int. Immunol., November 1, 2003; 15(11): 1389 - 1399. [Abstract] [Full Text] [PDF]
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J. S. Leon, K. Wang, and D. M. Engman Myosin Autoimmunity Is Not Essential for Cardiac Inflammation in Acute Chagas' Disease J. Immunol., October 15, 2003; 171(8): 4271 - 4277. [Abstract] [Full Text] [PDF]
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K. Roelofs-Haarhuis, X. Wu, M. Nowak, M. Fang, S. Artik, and E. Gleichmann Infectious Nickel Tolerance: A Reciprocal Interplay of Tolerogenic APCs and T Suppressor Cells That Is Driven by Immunization J. Immunol., September 15, 2003; 171(6): 2863 - 2872. [Abstract] [Full Text] [PDF]
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S. A. Quezada, B. Fuller, L. Z. Jarvinen, M. Gonzalez, B. R. Blazar, A. Y. Rudensky, T. B. Strom, and R. J. Noelle Mechanisms of donor-specific transfusion tolerance: preemptive induction of clonal T-cell exhaustion via indirect presentation Blood, September 1, 2003; 102(5): 1920 - 1926. [Abstract] [Full Text] [PDF]
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A. E. Morelli, A. T. Larregina, W. J. Shufesky, A. F. Zahorchak, A. J. Logar, G. D. Papworth, Z. Wang, S. C. Watkins, L. D. Falo Jr, and A. W. Thomson Internalization of circulating apoptotic cells by splenic marginal zone dendritic cells: dependence on complement receptors and effect on cytokine production Blood, January 15, 2003; 101(2): 611 - 620. [Abstract] [Full Text] [PDF]
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J. R. Kirman, T. Turon, H. Su, A. Li, C. Kraus, J. M. Polo, J. Belisle, S. Morris, and R. A. Seder Enhanced Immunogenicity to Mycobacterium tuberculosis by Vaccination with an Alphavirus Plasmid Replicon Expressing Antigen 85A Infect. Immun., January 1, 2003; 71(1): 575 - 579. [Abstract] [Full Text] [PDF]
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E. Mougneau, S. Hugues, and N. Glaichenhaus Antigen Presentation by Dendritic Cells In Vivo J. Exp. Med., October 21, 2002; 196(8): 1013 - 1016. [Full Text] [PDF]
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K. Liu, T. Iyoda, M. Saternus, Y. Kimura, K. Inaba, and R. M. Steinman Immune Tolerance After Delivery of Dying Cells to Dendritic Cells In Situ J. Exp. Med., October 21, 2002; 196(8): 1091 - 1097. [Abstract] [Full Text] [PDF]
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