| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
*
Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Japan;
Department of Immunology, Tokai University, Isehara, Japan; and
Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Studies on CD40- or CD40L-deficient mice and analysis of HIGM have established that interactions between CD40 on B cells and CD40L on activated T cells are essential for effective humoral immune responses, including Ag-specific Ab production, Ig class switching, and germinal center formation (11, 12, 13, 14). CD40-CD40L interactions play important roles in cellular immunity as well. For example, CD40 is expressed on various APCs (15, 16), thereby CD40-CD40L interactions are critically involved in T cell priming, activation, and differentiation into Th1 cells through the expression of various costimulatory molecules such as B7-1 and B7-2 on APCs and secretion of cytokines such as IL-12 (17, 18, 19, 20). Moreover, the prevalence of autoimmune diseases in HIGM patients suggests that CD40-CD40L interactions might be involved in the control of autoreactive lymphocytes. Although CD40- or CD40L-deficient mice appear to be a suitable model to explore autoreactivity in the absence of CD40-CD40L interactions, autoimmune diseases have not been reported either in CD40- or CD40L-deficient mice so far. One of the reasons for this is that coexisting impairments of T cell activation due to the lack of CD40-CD40L interactions (17, 18, 19, 20) would conceal autoreactivity and make it difficult to detect autoimmunity in such mice maintained in pathogen-free conditions.
To maintain immunological self-tolerance and avoid autoimmunity,
pathogenic self-reactive T cells are clonally deleted or rendered
anergic in the thymus and periphery (21, 22, 23, 24). T
cell-mediated control of self-reactive T cells also plays a significant
role in self-tolerance (25). For example, transfer of T
cells depleted of CD25+ cells or
CD45RBlow cells causes various autoimmune
diseases in recipient nude or scid mice, respectively, while
CD25+ CD45RBlow
CD4+ T cells can inhibit the development of
autoimmunity when cotransferred (26, 27). These
observations suggest that the CD25+
CD45RBlow CD4+ T cell
subpopulation may include regulatory T cells that suppress autoreactive
lymphocytes. Besides such regulatory T cells defined by expression
levels of cell surface markers, T cells producing inhibitory cytokines
may also act as regulatory T cells. A TGF-
-producing T cell subset,
called Th3, has been identified mainly in oral tolerance systems
(28). In addition, T regulatory cells 1 (Tr1) subset has
been recently identified and been generated in vitro (29).
Tr1 cells produce large amounts of IL-10 but small amounts of IFN-
and IL-4. Upon stimulation, Tr1 cells immediately produce IL-10, which
modulates activation of APCs and their expression of costimulatory
molecules (30).
In this report, we demonstrate significant increases in T cell autoreactivity in the absence of CD40-CD40L interactions. We show that autoimmune diseases can be induced by transferring T cells from CD40-deficient BALB/c mice into BALB/c athymic nude (nu/nu) mice which lack T cells but have B cells and other APCs expressing CD40. Furthermore, we show severe reduction of CD25+ CD45RBlow CD4+ T cells in CD40-deficient mice and impaired differentiation into Tr1 cells on CD40-deficient APCs. Our results indicate that defective development of regulatory T cells leads to increased T cell autoreactivity in the absence of CD40-CD40L interactions.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
To generate BALB/c CD40-deficient mice, CD40-deficient mice
(12) were crossed for more than 10 generations with BALB/c
mice purchased from SLC (Shizuoka, Japan). BALB/c nu/nu,
C57BL/6, or DBA/2 mice of 6 wk of age were also purchased from SLC.
Mice expressing the transgenic OVA
(OVA323–339)-specific 
TCR on a BALB/c
background were produced as previously described (31). All
of these mice were maintained in our animal facility and cared for in
accordance with institutional guidelines for animal welfare.
Preparation of T cells
Spleen cells were removed from wild-type or CD40-deficient BALB/c mice, C57BL/6, or DBA/2 mice and teased into single-cell suspensions. Erythrocytes were removed by hypotonic lysis. For enrichment of Thy-1+, CD45RBhigh or low CD4+, or CD62Lbright T cells, we isolated each fractions from the spleen cell suspensions using MACS or FACS sorting. The purity of the cells were checked using FACScan (Becton Dickinson, Mountain View, CA). The resulting purity was >95–98% in all experiments.
Titers of serum Abs
IgG anti-DNA at 12 wk after the transfer were determined by ELISA on sera diluted to 1:100, as previously described (27). Calf thymus DNA (Sigma, St. Louis, MO) was purified with a Sepa Gene kit (Nippon Gene, Toyama, Japan), and dsDNA was obtained by treating the DNA with S1 nuclease (Sigma). ssDNA was derived by boiling the DNA solution for 15 min followed by immediate immersion on ice. Wells of microtiter plates were coated with 5 µg/ml of either dsDNA or ssDNA. Similarly, serially diluted serum samples and control serum derived from MRL/lpr mice at 4 mo of age were incubated, followed by addition of AP-labeled anti-mouse IgG Abs (Southern Biotechnology Associates, Birmingham, AL). We defined serum titers of MRL/lpr mice at 4 mo of age as 1000 U/ml. Serum titers of autoantibodies specific for gastritic parietal cells were also assessed by ELISA as previously described (32). For detection of anti-CD40 Abs, wells of microtiter plates were coated with 5 µg/ml mouse CD40-human IgG Fc fusion protein (kindly provided by Dr. D. Gray (33)). Then diluted serum samples were incubated, followed by addition of AP-labeled anti-IgG Abs (Southern Biotechnology Associates).
In vivo priming of CD40-deficient mice
CD40-deficient or normal BALB/c mice were injected with
splenocytes (1 x 107 cells/mouse) of
CD40-deficient BALB/c, normal BALB/c, C57BL/6, or DBA/2 mice i.v. One
week after priming, CD4+ T cells were purified
from the primed mice and were stimulated with irradiated (3000 rad)
splenocytes from CD40-deficient mice, normal BALB/c, C57BL/6, or DBA/2
mice for 3 and 5 days at a ratio of 1:5. For proliferation assays,
cells were pulsed with 2 µCi of [3H]thymidine
for the last 12 h. For cytokine production, culture supernatants
from 3- or 5-day cultures were harvested and the levels of IFN- and
IL-10 were measured by ELISA kit (R&D Systems, Minneapolis,
MN).
Induction and in vivo transfer of Tr1 cells
CD62Lbright CD4+ T cells from OVA-TCR-transgenic BALB/c mice were sorted out by FACS and 1 x 105 cells of the isolated T cells were cultured with OVA peptide (323–339; 0.6 µM) and irradiated splenic APCs (5 x 106 cells) in the presence of IL-10 (100 U/ml) (PharMingen, San Diego, CA) in 24-well plates as previously described (29). The stimulation, under the same conditions, was repeated weekly for 3 consecutive weeks. For analysis of the effect of Tr1 cells on autoimmunity, the recipient nu/nu mice were injected i.v. with 100 µl of PBS containing 2 x 105 Tr1 differentiated cells with 5 x 106 cells of T cells from CD40-deficient mice. The recipient mice were orally treated with OVA (100 ng/ml) as previously described (29).
Flow cytometry and Abs
Single-cell suspensions were prepared from wild-type BALB/c or
CD40-deficient BALB/c spleens at 6 wk of age. After purification of
CD4+ cells using the MACS system, flow cytometric
analysis was performed using FACScan. Abs used for staining were
biotinylated anti-CD25 (7D4), CD45RB (16A), and PE-conjugated
streptavidin (PharMingen). Analysis of intracellular cytokines by flow
cytometry was performed using Golgi-plug kits (PharMingen). Briefly,
cells (105cells/ml) were activated with
immobilized anti-CD3 and anti-CD28 mAbs (PharMingen) for 6
h. Golgi-plug (PharMingen), containing brefeldin A was added for the
last 4 h of culture. Then cells were inoculated with the following
mAbs (PharMingen): PE-conjugated anti-IL-10 (JES-16E3),
FITC-conjugated anti-IL-4 (BAD-1D11), and FITC-conjugated
anti-IFN- (XMG1.2). Samples were analyzed on FACScan.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
To determine whether pathogenic self-reactive T cells have
developed in CD40-deficient mice, we transferred T cells from
CD40-deficient BALB/c mice into BALB/c nu/nu mice, thereby
reconstituting CD40-CD40L interactions between CD40L on T cells derived
from CD40-deficient mice and CD40 on B cells and APCs derived from the
recipient nu/nu mice. Twelve weeks after cell transfer,
significant titers of autoantibodies specific for ssDNA, dsDNA, or
gastric parietal cell Ags were observed in the nu/nu mice
inoculated with T cells from CD40-deficient mice (Fig. 1
). In contrast, the nu/nu
mice inoculated with T cells from wild-type mice did not produce these
autoantibodies. Macroscopically, all of the anti-parietal cell
Ab-positive mice had thick gastric mucosa from the fundus to the body
of the stomach. Gastric pH was neutral to alkaline, indicating
disruption and dysfunction of gastric parietal cells. Histological
analysis revealed severe gastritis with loss and damage of the parietal
cells and chief cells and marked infiltration of mononuclear
cells into the gastric mucosa (Fig. 2A). In addition,
histologically evident thyroiditis and sialoadenitis developed in
40–50% of mice (Fig. 2, B and C; Table 1). Some (
25%) recipients also
developed oophoritis, adrenalitis, or insulitis (Fig. 2, D–F). No autoimmunity developed in the nu/nu
mice inoculated with T cells from wild-type mice (Fig. 2, G–L). Furthermore, the autoimmunity could be induced by
CD4+ T cells alone but not
CD8+ T cells from CD40-deficient mice (data not
shown), indicating that CD4+ T cells are key
effector cells in the autoimmunity.
|
|
|
A). In addition, to determine
whether or not T cells from CD40-deficient mice respond to CD40
molecules, we primed CD40-deficient BALB/c mice with splenocytes from
CD40-positive BALB/c, CD40-deficient BALB/c, C57BL/6, or DBA/2 mice.
One week later, we examined MLR of T cells from the primed mice against
each priming lymphocyte (Fig. 3B). T cells from
CD40-deficient mice that were primed with BALB/c CD40-positive cells
neither proliferate nor produce IFN- in response to BALB/c
CD40-positive cells, indicating that CD40-deficient T cells did not
show MLR against CD40-positive cells. However, they reacted to
H-2d-matched or -mismatched allogenic splenocytes
of DBA/2 or C57BL/6 mice. Taken together, these results suggest that a
T cell response against CD40 molecules did not take place in the
present experimental system.
|
It has been shown that autoimmune diseases similar to those
produced in our experiments can be induced by simply transferring
CD25+ cell- or CD45RBlow
cell-depleted T cell suspensions from normal mice into recipient
nu/nu mice (25, 27, 34). This autoimmune
induction can be prevented by cotransfer of the eliminated population,
suggesting that the CD25+ or
CD45RBlow T cell subpopulation may contain
regulatory T cells capable of controlling autoreactive T cells
(25, 27, 34, 35). The CD25+
CD45RBlow CD4+ T cell
subpopulation was significantly reduced in CD40-deficient mice compared
with wild-type mice (Fig. 4), although
the lymphocytes from the former did not display any abnormality in the
phenotype of other surface markers, as previously described (data not
shown) (12). The CD25+
CD4+ T cells were included in
CD45RBlow CD4+ T cell
populations (data not shown) (27). To determine whether or
not the reduction of such subpopulations is responsible for the
increased autoreactivity, CD45RBlow
CD4+ T cells were purified from wild-type mice
and mixed with T cells from CD40-deficient mice at a physiological
ratio (1:5), and then transferred into nu/nu mice.
Cotransfer of the CD45RBlow
CD4+ T cells from wild-type mice almost
completely suppressed elevations in the titers of autoantibodies,
including anti-ssDNA, anti-dsDNA, anti-parietal cell
autoantibodies, and histologically evident gastritis development driven
by T cells from CD40-deficient mice (Fig. 5).
|
|
, we could not detect any significant differences in the ability of
CD45RBhigh T cells to induce autoimmunity between
wild-type and CD40-deficient mice. Collectively, CD40-CD40L
interactions appear to be required for generating regulatory T cells
that negatively regulate T cell autoreactivity.
|
A recent study established a regulatory T cell subset, Tr1, which
produces high levels of an inhibitory cytokine, IL-10, but not IFN-
or IL-4 (29). Tr1 cells were induced in vitro by Ag
stimulation in the presence of IL-10 and inhibited
CD45RBhigh cell-induced colitis. To determine the
ability of CD40-deficient APCs to induce Tr1,
CD62Lbright CD4+ naive T
cells of OVA-specific TCR-transgenic mice were stimulated with an OVA
peptide plus CD40-deficient or wild-type APCs in the presence of IL-10.
After 3 wk of consecutive stimulation, T cells were harvested,
restimulated with anti-CD3 and anti-CD28 Abs, and stained for
detection of intracellular cytokines. Fig. 7 shows that wild-type APCs could
predominantly induce the Tr1 subset characterized by high levels of
IL-10 and low levels of IFN- or IL-4, as previously described
(29). On the other hand, instead of the Tr1 subset,
Th2-like cells secreting high levels of IL-4 and IL-10 predominantly
developed on CD40-deficient APCs. Even 1 wk after stimulation,
CD40-deficient APCs induced a significant number of Th2 cells (data not
shown). This preferential induction of Th2 cells on CD40-deficient APCs
is in accord with the previous observations that CD40- or
CD40L-deficient mice mount Th2 responses instead of Th1 responses
because of a lack of IL-12 production by APCs (18, 19).
Cytokine secretion of Tr1-differentiated cells on the wild-type APCs
showed a typical Tr1-type cytokine profile (IL-10, 1080 ± 110
pg/ml; IL-4, <50 pg/ml; IFN-, <8 pg/ml; and TGF-, 660 ±
110 pg/ml). In contrast, Th2-differentiated cells on CD40-negative APCs
showed a Th2-type cytokine profile (IL-10, 520 ± 100 pg/ml; IL-4,
1280 ± 125 pg/ml; IFN-, <8 pg/ml; and TGF-, 768 ±
100 pg/ml).
|
, OVA-specific Tr1
cells inhibited the elevations of autoantibodies against ssDNA, dsDNA,
and parietal cells and histological development of gastritis only when
the recipients received OVA. These results collectively suggest that
this failure to induce Tr1 might contribute to elevated T cell
autoreactivity in CD40-deficient mice.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The Tr1 subset has been functionally characterized by their secretion of high levels of IL-10. Although there is substantial data that regulatory CD25+ CD45RBlow CD4+ T cells control other T cells by a cognate cellular interaction on APCs (25, 36, 37), the relationship between the CD25+ CD45RBlow CD4+ T cell subpopulation and the Tr1 population remains to be determined. The Tr1 subset can be induced by in vitro stimulation with APCs and specific Ags in the presence of IL-10 and can inhibit CD45RBhigh CD4+ T cell-induced autoimmunity (29). Unlike Th1 or Th2 cells that emerged from 1-wk in vitro culture without IL-10 (data not shown), development of Tr1-like cells required at least 3 wk on CD40-positive APCs in the presence of IL-10, as reported previously (29). Moreover, Tr1 cells proliferate poorly presumably due to their IL-10 production (29). This delayed induction and poor proliferative capacity of Tr1 cells may allow autoreactive T cells from CD40-deficient mice to expand rapidly, to differentiate into Th1 or Th2 effector cells, and thereby to cause autoimmune responses in nu/nu recipients. Thus, our results indicate that CD40-CD40L interactions are required for generation of regulatory T cells. However, a very small number of CD25+ CD45RBlow CD4+ T cells could be detected in CD40-deficient mice. At present, it is unclear whether or not these residual CD25+ CD45RBlow CD4+ T cell subpopulations in CD40-deficient mice contain functional regulatory T cells because of difficulty in enrichment of enough numbers of these populations from CD40-deficient mice for the in vivo functional analysis. Further studies will be necessary to address this question.
In addition to defects in generating regulatory T cells presented here,
there are two other possible mechanisms that may underlie the ability
of T cells from CD40-deficient mice to induce autoimmunity. First,
autoimmune diseases observed here may be due to responses of T cells
which are not tolerant to the CD40 molecule. However, there were no
differences in the titers of anti-CD40 Abs between the
nu/nu mice inoculated with T cells from either
CD40-deficient or wild-type mice T cells. In addition, T cells from
CD40-deficient mice failed to react with CD40-positive cells even when
in vivo primed (Fig. 3
). These results suggest that T cell responses
against CD40 molecules did not take place in our experiments. Second,
impaired clonal deletion and peripheral anergy might be the cause of
autoimmunity. A previous report has shown that the lack of CD40-CD40L
interactions affects thymic deletion of T cells reactive to several
endogenous Ags (38). However, there was no significant
abnormality in deletion of T cells expressing V11 and V12 TCR
reactive to endogenous Mls in CD40-deficient BALB/c mice. T cells
expressing V8 TCR were also eliminated in CD40-deficient mice when
staphylococcal enterotoxin B was systemically injected (our unpublished
results). A recent study has shown that CD40 deficiency only affects
negative selection of T cells reactive to weakly stimulating
superantigens presented by B cells but not to strongly stimulating Ags
(39). As for peripheral anergy, it has been shown to
require adequate activation of autoreactive T cells (40).
Autoreactive T cells may not undergo activation before clonal anergy in
CD40-deficient mice because of impaired CD40-CD40L interactions,
resulting in accumulated nontolerized T cells. However, severity and
pathological features of autoimmune diseases induced by unfractionated
T cells or CD45RBhigh T cells of CD40-deficient
mice were very similar to those of diseases induced by
CD45RBhigh T cells from normal BALB/c mice (Fig. 6) (27, 34). Thus, autoimmune diseases induced by T cells
of CD40-deficient mice may not be further modified or enhanced by GVH
reactions against CD40 molecules or by enhanced production of
autoreactive T cells due to impaired clonal deletion or anergy.
Patients with HIGM not only produce various autoantibodies, but also succumb to various autoimmune diseases (1, 2). Thus, CD40- and CD40L-deficient mice may be expected to be susceptible to autoimmune diseases. However, autoimmune diseases have not been detected in CD40-deficient mice possibly because activation of autoreactive T cells is severely affected in CD40- or CD40L-deficient mice (41, 42, 43). In CD40-deficient mice, therefore, reactive T cells may fail to differentiate into pathogenic effector cells. HIGM patients frequently suffer from persistent infections by various kinds of pathogens, some of which might stimulate T cells without CD40-CD40L interactions, resulting in accumulated autoreactive T cell responses. In fact, several pathogens such as lymphocytic choriomeningitis virus and murine CMV have been reported to induce fully functional CD4+ effector T cells without CD40-CD40L interactions (44, 45), suggesting that the lack of CD40-CD40L interactions in T cell activation might be compensated by other stimuli. Since CD40- or CD40L-deficient mice maintained in pathogen-free conditions cannot be stimulated by these pathogens, it may be difficult to trigger autoimmunity in these mice. Alternatively, production of high-affinity IgG autoantibodies may be necessary for full-blown autoimmune diseases mediated by T cells. For instance, CD40-dependent Ab production has been shown to be involved in tissue-specific infiltration of autoreactive T cells in the autoimmune arthritis model (46). Thus, defective Ab production might also conceal T cell-mediated autoimmune diseases in CD40-deficient mice.
In conclusion, we have presented evidence that the lack of CD40-CD40L interactions can cause increased autoreactivity despite immunodeficiency. The relationship between immunodeficiency and autoimmunity has been a paradoxical phenomenon. It is difficult to treat patients of immunodeficiency accompanied by autoimmune diseases because immunosuppressive drugs must be used despite immunodeficiency (1). The present study will provide clues for understanding the pathogenesis of autoimmune complications in immunodeficiency and contribute to developing better treatments.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
2 A.K., X.W., and I.L. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Hitoshi Kikutani, Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
4 Abbreviations used in this paper: HIGM, X-linked hyper-IgM syndrome; CD40L, CD40 ligand; Tr1, T regulatory cells 1; GVH, graft-versus-host.
Received for publication May 31, 2000. Accepted for publication October 6, 2000.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
-chains (CD25): breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J. Immunol. 155:1151.[Abstract]
This article has been cited by other articles:
|
|
 |
|
  A. Dolganiuc and G. Szabo T cells with regulatory activity in hepatitis C virus infection: what we know and what we don't J. Leukoc. Biol., September 1, 2008; 84(3): 614 - 622. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. N. Golovina, T. Mikheeva, M. M. Suhoski, N. A. Aqui, V. C. Tai, X. Shan, R. Liu, R. R. Balcarcel, N. Fisher, B. L. Levine, et al. CD28 Costimulation Is Essential for Human T Regulatory Expansion and Function J. Immunol., August 15, 2008; 181(4): 2855 - 2868. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A Tulunay, S Yavuz, H Direskeneli, and E Eksioglu-Demiralp CD8+CD28-, suppressive T cells in systemic lupus erythematosus Lupus, July 1, 2008; 17(7): 630 - 637. [Abstract] [PDF]
|
|
|
|
|
|
H. Jin, Y. Kang, L. Zhao, C. Xiao, Y. Hu, R. She, Y. Yu, X. Du, G. Zhao, T. Ng, et al. Induction of Adaptive T Regulatory Cells That Suppress the Allergic Response by Coimmunization of DNA and Protein Vaccines J. Immunol., April 15, 2008; 180(8): 5360 - 5372. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. U. A. Mollah, S. Pai, C. Moore, B. J. O'Sullivan, M. J. Harrison, J. Peng, K. Phillips, J. B. Prins, J. Cardinal, and R. Thomas Abnormal NF-{kappa}B Function Characterizes Human Type 1 Diabetes Dendritic Cells and Monocytes J. Immunol., March 1, 2008; 180(5): 3166 - 3175. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Hanig and M. B. Lutz Suppression of Mature Dendritic Cell Function by Regulatory T Cells In Vivo Is Abrogated by CD40 Licensing J. Immunol., February 1, 2008; 180(3): 1405 - 1413. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. J. Spence and E. A. Green Foxp3+ regulatory T cells promiscuously accept thymic signals critical for their development PNAS, January 22, 2008; 105(3): 973 - 978. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Herve, I. Isnardi, Y.-s. Ng, J. B. Bussel, H. D. Ochs, C. Cunningham-Rundles, and E. Meffre CD40 ligand and MHC class II expression are essential for human peripheral B cell tolerance J. Exp. Med., July 9, 2007; 204(7): 1583 - 1593. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Zhan, D. Bourges, J. A. Dromey, L. C. Harrison, and A. M. Lew The origin of thymic CD4+CD25+ regulatory T cells and their co-stimulatory requirements are determined after elimination of recirculating peripheral CD4+ cells Int. Immunol., April 1, 2007; 19(4): 455 - 463. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Huber, A. M. Feldman, and D. Sartini Coxsackievirus B3 Induces T Regulatory Cells, Which Inhibit Cardiomyopathy in Tumor Necrosis Factor-{alpha} Transgenic Mice Circ. Res., November 10, 2006; 99(10): 1109 - 1116. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Chiodoni, M. Iezzi, C. Guiducci, S. Sangaletti, I. Alessandrini, C. Ratti, F. Tiboni, P. Musiani, D. N. Granger, and M. P. Colombo Triggering CD40 on endothelial cells contributes to tumor growth J. Exp. Med., October 30, 2006; 203(11): 2441 - 2450. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Toda and C. A. Piccirillo Development and function of naturally occurring CD4+CD25+ regulatory T cells J. Leukoc. Biol., September 1, 2006; 80(3): 458 - 470. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Lesley, L. M. Kelly, Y. Xu, and J. G. Cyster Naive CD4 T cells constitutively express CD40L and augment autoreactive B cell survival PNAS, July 11, 2006; 103(28): 10717 - 10722. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Veldhoen, H. Moncrieffe, R. J. Hocking, C. J. Atkins, and B. Stockinger Modulation of Dendritic Cell Function by Naive and Regulatory CD4+ T Cells J. Immunol., May 15, 2006; 176(10): 6202 - 6210. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Akiba, K. Takeda, Y. Kojima, Y. Usui, N. Harada, T. Yamazaki, J. Ma, K. Tezuka, H. Yagita, and K. Okumura The Role of ICOS in the CXCR5+ Follicular B Helper T Cell Maintenance In Vivo J. Immunol., August 15, 2005; 175(4): 2340 - 2348. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Verginis, H. S. Li, and G. Carayanniotis Tolerogenic Semimature Dendritic Cells Suppress Experimental Autoimmune Thyroiditis by Activation of Thyroglobulin-Specific CD4+CD25+ T Cells J. Immunol., June 1, 2005; 174(11): 7433 - 7439. [Abstract] [Full Text] [PDF]
|
|
) from the same litter were added to microtiter plates coated with
mouse CD40-human IgG Fc fusion proteins, and bound Abs were detected
using ELISA. B, T cells from CD40-deficient mice did not
respond to CD40-positive cells. CD40+/+ BALB/c, and
CD40-/- BALB/c mice were primed with splenocytes of
CD40-/- (
), CD40+/+ (
) BALB/c mice,
C57BL/6 (•), or H-2d-matched DBA/2 (
