| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Walter and Eliza Hall Institute of Medical Research, Royal Melbourne Hospital, Parkville, Australia
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
CD4 help for induction of cross-primed CTL can be potentiated by costimulatory molecules (such as CD40) on APCs (2, 3, 4). The B7 and CD40 costimulatory pathways can act independently of each other (8) or influence each other. For example, modulation of CD40 can up-regulate B7 on APC (9, 10, 11); and CTLA4Ig, a negative regulator of B7/CD28 interaction, can block the ability of anti-CD40 Ab to stimulate CTL (3). Conversely, ligation of CD28 can induce CD40L expression (12). These findings not only illustrate a pathway whereby CD4 help for CD8 cell activation is educed via APCs, but also reinforce the importance of costimulation for activation of naive CD8 T cells. Nevertheless, costimulation blockade does not always prevent CD8 activation and allograft rejection. For example, in a TCR Tg/RAG-/- mouse, induction of CTL was not affected by CTLA4Ig treatment (7).
Independence of CD4 help and costimulation for CTL induction in TCR Tg mice could be simply due to the sheer abundance of CTL precursors with high intrinsic affinity to a single Ag. In such mice, costimulation-dependent population expansion that is critical for a normal immune response may not be necessary. Thus, we reassessed in this study the requirement of CD4 help and costimulation for CTL induction to allogeneic tumor P815 in wild-type mice (in which the T cell frequency is more representative of an allograft recipient) compared with a novel CD4-deficient mouse. To investigate the role of costimulation and CD4 help, we have generated a novel CD4-deficient mouse that is Tg for a rat anti-mouse CD4 Ab (GK1.5). These GK mice have a permanent absence of peripheral CD4 cells without the residual Th cells present in commonly used CD4-/- mice (13) and MHC class II-/- mice (14, 15). Requirement of B7/CD28 costimulation for CTL induction in the presence or absence of CD4 cells was evaluated in CTLA4Ig Tg mice and in double Tg GK/CTLA4Ig mice. The role of CD40/CD40L interaction in the induction of CTL in the presence and the absence of CD4 cells was evaluated with blocking anti-CD40L Ab.
We show in this study that although CTL responses to allogeneic P815 tumor cells were optimal and more rapid with the presence of CD4 cells, they can be induced in their absence. This CD4 cell-independent CTL induction, however, is absolutely dependent on direct costimulation of B7/CD28, whereas CD40/CD40L is involved in both CD4-dependent and CD4-independent pathways.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
C57BL/6 mice with mutations in MHC class I:C.H-2bm1 (termed bm1) were used as wild-type mice. All Tg mice were produced on this bm1 background. The light chain was derived from the rat mAb GK1.5, and the heavy chain was a fusion of the VH of GK1.5 to C region of mouse IgG2c (16) and shown to be functional by transfection (17). The genes were cloned behind the human CMV promoter to generate GK Tg mice. CTLA4Ig Tg mice have previously been described (18). These mice respectively produce anti-CD4 Ab and CTLA4Ig abundantly into the circulation (see below). Doubly Tg mice were produced by crossing between homozygous GK and homozygous CTLA4Ig mice. BALB/c mice (H-2d) were used as donor and source of stimulator for MLR. These animals were bred under specific pathogen-free conditions at our Institute.
Cell lines and Abs
P815 (H-2d) is a mastocytoma-derived tumor line; EL-4 (H-2b) is a thymoma-derived cell line. Cell lines were maintained in DMEM supplemented with 10% FCS and 5 mM HEPES. The mAb 53-6.7 and YT169 (anti CD8), and MR1 (anti-CD40L) for in vivo experiments were produced in our laboratory. YTA3.1.2 is an anti-CD4 Ab that recognizes a different epitope to GK1.5 (19) and was used to confirm depletion of CD4 cells. The conjugated Abs 53-6.7 (anti-CD8) and H129 (anti-CD4) were purchased from Sigma (St. Louis, MO); the conjugated Abs Mel-14 (anti-CD62L), IM7 (anti-CD44), PC61 (anti-CD25), H57-595 (anti-TCRß), and 34-2-12 (anti-H-2Dd) were purchased from PharMingen (San Diego, CA).
Assessment of CTL function in vivo by clearance of target cells
Mice were injected i.p. with 5 x 106 P815 cells and killed at various times. Peritoneal cells were harvested by lavage and counted; numbers of surviving P815 cells were calculated from the percentage of H-2Dd-positive cells, as determined by FACS. Spleens were removed for cell culture and FACS analysis of CD8 cells. In some experiments, mice were treated with 0.5 mg of anti-CD40L Ab each on days 0 and 3 relative to P815 injection.
Cell culture
Splenocytes from P815-primed and unprimed animals were cultured at 5 x 106 cells/ml in 2 ml vol with 106 irradiated (200 Gy) P815 cells or 5 µg/ml anti-CD3 (145-2C11). Culture supernatants were harvested at various times after culture, and cytokine levels in the supernatants were evaluated. In some cases, living cells were harvested from the bulk culture and their lytic activity was assayed.
Assessment of CTL activity in vitro
For testing direct killing of targets, spleen cells from in vivo primed animals were prepared and used as effectors in the standard 4-h 51Cr release assay. As targets, P815 and control EL-4 cells were labeled with 51Cr for 90 min at 37°C and 104 cells were incubated with various numbers of effector cells in 96-well round-bottom plates for 4 h. Supernatants after plate centrifugation were harvested and assayed for specific lysis. For measuring CTL precursors, splenocytes from in vivo primed animals were cultured at 5 x 106 cells/ml in 2 ml vol with 106 irradiated (200 Gy) P815 cells for 6 days. After this in vitro stimulation, cells were assayed for lytic activity to P815 and EL-4 cells, as above.
FACS analysis of lymphoid cells
Leukocyte suspensions of spleen, lymph nodes, and peritoneal lavage were stained with mAb to CD4, CD8, CD62L, CD44, and CD25. Accumulation of P815 cells in peritoneal lavages was evaluated by the percentage of H-2d+ cells. Stained cells were analyzed on a FACScan (Becton Dickson, Mountain View, CA) with CellQuest software.
Cytokine ELISA
IL-2, IL-5, and IFN-
were assayed by ELISA, according to
manufacturer’s instruction. Recombinant cytokines as standard, coating
Ab, and biotinylated Ab were obtained from PharMingen.
Ab response to NP
To test helper actvity of GK mice, mice were immunized with 50 µg of alum-precipitated (4-hydroxy-3-nitrophenol) acetyl (NP) conjugated to keyhole limpet hemocyanin (KLH) (NP:KLH ratio 15:1). Serum Abs with high affinity for NP were detected with NP2-BSA-coated plates, as described previously (20).
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
We generated mice that were Tg for a chimeric rat anti-CD4 Ab
(derived from mAb GK1.5; hence the name GK mice) as a novel model of
CD4 deficiency. Under the human CMV promoter, the Ab was produced
predominantly in the pancreas (by Northern analysis) and reached levels
of 0.1 mg/ml in the circulation. These mice lack peripheral CD4 cells
(Fig. 1
A) and lack the
residual helper cell populations mentioned above, viz CD4 cells in MHC
class II-/- mice and the double negative
population in CD4-/- mice (Fig. 1, B
and C). The profiles with three anti-CD4 mAbs (YTA3.1.2,
H129, and GK1.5) were similar; critically, YTA3.1.2 sees a different
epitope to GK1.5 (19). The CD8 population was not
significantly changed in peripheral lymphoid organs compared with
wild-type mice. Mice doubly Tg for anti-CD4 Ab and CTLA4Ig
(GK/CTLA4Ig) were also produced and their CD4 phenotype was the same as
GK mice (Fig. 1A).
|
D). CTL induction and allogeneic tumor clearance were delayed in CD4-deficient mice
To examine whether CD8 CTL to P815 cells could be induced in the
absence of CD4 cells, both wild-type bm1 mice and CD4 cell-deficient GK
mice were injected i.p. with 5 x 106 P815
cells. Allogeneic tumor growth was quantitatively monitored by
peritoneal lavage. In bm1 mice, tumor cells were cleared 2 wk after
injection. In contrast, tumor clearance was slower in GK mice compared
with wild-type bm1 mice (Fig. 2). At 1
wk, P815 cells in GK mice were 7-fold more abundant than in wild-type
bm1 mice (Fig. 2A). P815 cells had been totally cleared in
wild-type mice by 2 wk (Fig. 2A), whereas it required an
additional 1–2 wk in GK mice. The rejection of P815 cells in GK mice
was indeed mediated by CD8 cells, as depletion of CD8 cells by mAb
treatment prevented the elimination of allogeneic tumor cells (Fig. 2B).
|
A). A standard CTL assay (6
days in vitro stimulation followed by chromium release assay) was used
to detect CTL precursors. CTL precursors to P815 cells could be
detected much earlier (6 days after injection) for both bm1 mice and GK
mice. Whereas splenocytes harvested at that time showed no direct
killing of P815 cells, CTL effectors did develop after in vitro
stimulation (Fig. 3B).
|
B). It was noted that CD8
expression was also down-regulated on the
CD62Llow cells (Fig. 4B). This is not
surprising, as activated CD8 cells have been found previously to
down-regulate CD8 (22). Activated CD8 cells were high in
CD44 and CD25 expression as well (data not shown).
|
production by splenocytes after 72-h
culture was also only detected in bm1 mice (2.2 ng/ml), but not in GK
mice (<0.1 ng/ml). In support of this role of IL-2, addition of
exogenous IL-2 improved the response of CD8 cells from our
CD4-deficient mice in vitro (see below). Treatment with blocking anti-CD40L Ab suppressed CTL induction and clearance of allogeneic cells in wild-type and CD4-deficient mice
During cross-priming of CD8 cells, CD40L and CD40 interaction
between CD4 cells and APC results in APC activation and then indirectly
helps CD8 activation (2, 3, 4). In some cases, direct
CD40L/CD40 interaction between CD8 cells and APC can occur (23, 24). To examine how CD40L/CD40 interaction contributes to CTL
induction to allogeneic MHC Ag, both bm1 mice and GK mice were treated
with anti-CD40L Ab, MR1. Two injections of 0.5 mg MR1 resulted in
delayed tumor rejection in both bm1 mice and GK mice, although numbers
of tumor cells in GK mice were significantly higher than in bm1 mice.
At 2 wk after P815 injection, the numbers of P815 cells that
accumulated in the peritoneal cavity of MR1-treated wild-type mice and
GK mice were 22 and 50 million, respectively (Fig. 5A). As a measurement of in
vivo effector function, splenocytes were tested for direct killing
immediately ex vivo in a chromium release assay (no in vitro culture).
CTL induction in MR1-treated mice was greatly inhibited for both
wild-type and GK mice (Fig. 5B). The proportion of
CD62Llow CD8 cells was also reduced (Fig. 4B). Furthermore, presumably because of reduced expansion
after priming, the percentage of CD8 cells in MR1-treated P815-primed
mice (whether wild-type or GK) was one-half that in corresponding
untreated P815-primed mice (Fig. 4A). With no significant
change in total numbers of splenocytes (all about 1.2 x
108), the decreased percentage reflects a
decrease in absolute numbers of CD8 cells. We conclude that direct
CD40L/CD40 interaction between CD8 cells and APC is critical for CTL
induction in the absence or presence of CD4 help.
|
CTLA4Ig prevented CTL induction and clearance of allogeneic cells in CD4-deficient mice, but not wild-type mice
The B7/CD28 costimulation pathway has been studied extensively and represents one of the major pathways for T cell costimulation (25). B7 blockade with fusion protein CTLA4Ig has been shown to inhibit or prevent the rejection of allo- and xenografts (26, 27). However, graft rejection can still occur in the absence of B7/CD28 costimulation (7, 28). We examined in this study in an allogeneic tumor model whether CD8 cell activation in the absence of CD4 help is sensitive to costimulation blockade by CTLA4Ig.
We have previously produced mice Tg for CTLA4Ig under the rat insulin
promoter (18). Islets from these mice inhibited MLR in
vitro (18). In these mice, CTLA4Ig secreted by the
pancreatic islets led to circulating CTLA4Ig that could be detected by
binding splenocytes, previously stimulated by LPS to up-regulate CD86
(B7-2) (Fig. 6A). Because the
detection method could potentially underestimate levels of CTLA4Ig due
to saturation of B7 epitopes, serum samples were serial diluted for
testing their CTLA4Ig levels. Based on mean fluorescence intensity at
sample dilution (1 in 10) that B7 binding was unsaturated, Fig. 6B showed that CTLA4Ig Tg mice and GK/CTLA4Ig doubly Tg mice
had a comparably high level of circulating CTLA4Ig before and 2 wk
after injection of tumor cells. The levels of CTLA4Ig in Tg mice
correspond to 0.1 mg/ml serum.
|
). In contrast, GK/CTLA4Ig doubly Tg
mice failed to reject the P815 cells; indeed, the P815 cells multiplied
to be 2 x 108 in the peritoneum (Fig. 7A). By about 4 wk, these mice succumbed to the tumor
burden. This was in accord with the low numbers of activated CD8 cells
(Fig. 7B) and the lack of CTL induction in GK/CTLA4Ig Tg
mice (Fig. 8B).
|
|
As shown above, splenocytes isolated from wild-type and GK mice
early on (6 days post-P815 injection) contained very few mature CTL
effectors, but they did contain CTL precursors that matured into
effectors after in vitro culture. It is possible that splenocytes from
doubly Tg mice were also primed to become CTL precursors, but did not
mature into effectors in vivo. To investigate this possibility,
splenocytes from primed doubly Tg mice were cultured with irradiated
P815 cells and/or IL-2. Addition of exogenous IL-2 (1 ng/ml) was
required for CD8 cells to expand, to become killers, and to secrete
IFN- ; there was no response when P815 cells alone were used
(Fig. 8).
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
ß+
cells (13, 30, 31). CD8 cells in
CD4-/- mice can also be MHC class
II restricted (32). These minor populations can function
as helpers, and therefore may represent a problem in interpretation of
results, especially in vivo, in which such minor populations can be
readily expanded. This may also explain why allograft rejection is
found to be delayed in mice whose CD4 cells are depleted by Ab, but not
in MHC class II-deficient mice and CD4-deficient mice
(33). Our results indicate that CD4 cells provide help in the induction of CTL against allogeneic P815 cells. In response to allogeneic cells, requirement of CD4 help for CTL induction may vary with precursor frequency. When there are abundant Ag-specific cells, e.g., in anti-Ld TCR/RAG Tg mice (2C), and thus expansion is less important, optimal CTL response and P815 tumor clearance are achieved without the involvement of CD4 cells (7). When there are fewer cells, e.g., in adoptive transfer experiments into syngeneic mice with only few (4, 5, 6, 7, 8) million of TCR Tg cells, alloreactive stimulated expansion of the transferred cells was critically dependent on cotransfer of CD4 cells (6). In our study in which H-2d+ P815 cells are injected into fully mismatched MHC wild-type bm1 mice, the abundance of T cells capable of recognizing alloantigen in recipient mice probably falls between the above two systems. An alloreactive CTL response develops in mice lacking peripheral CD4 cells, and the response is sufficient to clear the tumor cells. However, development of CTL response in the absence of CD4 cells is suboptimal and delayed when compared with wild-type mice, reflecting the need of CD4 help for expansion of activated CD8 cells and optimal CTL response. The delay in CTL induction may have been the reason that CTL were not detected in CD4 cell-depleted mice in an earlier study (5). The results from CD4 cell-deficient mice are reminiscent of CTL responses to some viral infections that are believed to be CD4 independent. For example, although both CD4 cell-deficient and wild-type mice are capable of mounting CTL to clear influenza infection, the numbers of responding CTL precursors were much lower in CD4 cell-deficient mice (34). Similarly, a primary CTL response to acute lymphocytic choriomeningitis virus infection was produced in CD4 cell-deficient mice, and this was sufficient to clear infection. However, in the absence of CD4 cells, the CTL response was not sustained and infection could persist (35, 36). One conclusion that befits all of these findings is that the major contribution of CD4 cell help for optimal CTL induction is facilitating population expansion.
One way that CD4 cells provide help is through the provision of
cytokines such as IL-2 (37, 38). In the above 2C T cell
adoptive transfer study, in vivo expansion of transferred cells was
largely related to the ability of cotransferred CD4 cells to produce
IL-2, as CD4 cells from IL-2-/- mice did not
result in the expansion of 2C cells (6). In our study,
P815-primed bm1 splenocytes that contain both CD4 and CD8 cells
produced much more IL-2 than cells from CD4 cell-deficient mice. It is
plausible that IL-2 produced by CD4 cells may enhance CTL responses by
expansion of activated precursors. Indeed, we have shown that CD8
cells, either naive or primed, proliferate and become effectors in
vitro in response to stimulation by P815 alloantigen and IL-2 (Fig. 8),
whereas naive CD8 cells did not respond to alloantigens from P815
without exogenous IL-2 (data not shown). Although IL-2 can also
directly enhance cellular cytotoxicity of CD8 cells as well
(39), the amount of IL-2 required for generation of killer
activity is 10-fold lower than the amounts of IL-2 required for
proliferation (40).
Another pathway in which CD4 cells provide help for CD8 cells is via activation of APCs. CD40/CD40L interaction between CD4 cells and APCs has been demonstrated to be critical for in vivo CD8 priming (2, 3, 4), although CD40-independent mechanisms may also exist (41). Ligation of CD40 by an agonist anti-CD40 Ab can restore CD8 CTL activities in CD4 T cell-depleted mice (2, 3, 4). In our study, interruption of CD40/CD40L interaction by anti-CD40L Ab resulted in failure to clear tumor cells and to induce CTL response, notably both in the presence and the absence of CD4 cells. This suggested that in addition to the known role of CD40/CD40L in CTL induction via indirect interaction through APC and CD4 cells (2, 3, 4), there can be direct interaction of CD40/CD40L between APC and CD8 cells (23, 24), although in normal circumstances this direct pathway may be masked by the CD4 pathway. As for strong CTL inducers such as lymphocytic choriomeningitis virus, Pichinde virus, or vesicular stomatitis virus, mice can mount CTL responses in CD40L-knockout mice, but the memory CTL response was much less efficient than in wild-type mice (42).
The development of CTL responses to allogeneic Ags in the absence of CD4 help poses the important question of whether the CD4 cell-independent CTL response is dependent on costimulation. Optimal T cell activation is believed to require two signals: ligation of TCR to MHC/peptide complex (signal 1) and costimulation (signal 2). Several reports have described activation of CD8 cells without the need for costimulation, but this requires high dose or persistent Ag exposure and the use of TCR Tg mice (7, 43, 44, 45, 46). In contrast, only in the presence of costimulation can low concentrations of allopeptides induce high CD69 expression, proliferation, and high IL-2 production (43, 45). Others have also pointed to a critical role of costimulation in induction of CD8 CTL (47, 48). A cogent example is in a syngeneic tumor system, in which without CD4 help, induction of CTL responses was effective, only when the MHC class I+ and class II- tumor cells were transfected with B7 (47) (although this may still require involvement of B7-expressing host APC (49, 50)). As discussed above for CD4 dependence, these results can be largely reconciled by the premise that lack of costimulation can be compensated for by a very strong signal 1 at the total population level (abundant specific T cells and high Ag dose). In our study, CTL induction to allogeneic tumor cells in the absence of CD4 cells was totally abrogated by B7 being blocked by circulating CTLA4Ig; thus, the allogeneic tumor cells persisted for a long time in our study and indeed mice were overcome by the tumor burden. The main contribution of CD28-mediated signaling is to promote the release of IL-2, which in turn expands activated CTL (51). As already mentioned above, the expansion process that may be less important when the cells are very abundant (preexpanded) such as in TCR Tg. We believe that without using TCR Tg models, our experimental setting is more representative of an allograft into a transplant recipient and that induction of CTL to allogeneic tumor cells in the absence of CD4 cell help is critically dependent on the B7/CD28 costimulation pathway.
Interestingly, CD8 activation is blocked by Tg CTLA4Ig, only when CD4 cells are absent. This is reminiscent of some studies that show that CTLA4Ig is only effective in blocking transplant rejection when host CD4 cells are depleted (52, 53). We do not believe that this is simply due to CD4 cells consuming CTLA4Ig, because we can easily detect free CTLA4Ig in non-CD4-deficient mice. One possible explanation is that in the absence of CD28, costimulation of CD4 cells can be mediated via CD40 (54, 55), and so the lack of B7/CD28 costimulation in CD8 cells is compensated for by this CD4 help.
The current study concludes that generation of alloreactive CD8 effectors can be independent of CD4 help, and that CD8 cell activation without CD4 cell help is more sensitive to costimulation blockade. In our allogeneic system, CD40/CD40L has a role in CTL priming for both CD4-dependent and CD4-independent responses, but B7/CD28 is critical for the CD4-independent pathway only. These influences should be considered in alloimmunity under different transplantation settings in the hope of more successful intervention.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
2 Address correspondence and reprint requests to Dr. A. Lew, Walter and Eliza Hall Institute of Medical Research, Post Office, Royal Melbourne Hospital, Parkville 3050, Australia.
3 Abbreviations used in this paper: Tg, transgenic; KLH, keyhole limpet hemocyanin; NP, (4-hydroxy-3-nitrophenol) acetyl.
Received for publication May 1, 2000. Accepted for publication July 10, 2000.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
during the differentiation of cytotoxic T lymphocytes induced by allografts. J. Immunol. 148:2348.[Abstract]
This article has been cited by other articles:
|
|
 |
|
  A. E. Gelman, M. Okazaki, J. Lai, C. G. Kornfeld, F. H. Kreisel, S. B. Richardson, S. Sugimoto, J. R. Tietjens, G. A. Patterson, A. S. Krupnick, et al. CD4+ T Lymphocytes Are Not Necessary for the Acute Rejection of Vascularized Mouse Lung Transplants J. Immunol., April 1, 2008; 180(7): 4754 - 4762. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. P. Tan, J. Pedersen, Y. Zhan, A. M. Lew, M. J. Pearse, O. L. C. Wijburg, and R. A. Strugnell CD8+ T Cells Are Associated with Severe Gastritis in Helicobacter pylori- Infected Mice in the Absence of CD4+ T Cells Infect. Immun., March 1, 2008; 76(3): 1289 - 1297. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Zhai, Y. Wang, Z. Wu, and J. W. Kupiec-Weglinski Defective Alloreactive CD8 T Cell Function and Memory Response in Allograft Recipients in the Absence of CD4 Help J. Immunol., October 1, 2007; 179(7): 4529 - 4534. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. H. Horne, M. A. Koester, K. Jayashankar, K. E. Lunsford, H. L. Dziema, and G. L. Bumgardner Disparate Primary and Secondary Allospecific CD8+ T Cell Cytolytic Effector Function in the Presence or Absence of Host CD4+ T Cells J. Immunol., July 1, 2007; 179(1): 80 - 88. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. G. H. Hernandez, L. Shen, and K. L. Rock CD40-CD40 Ligand Interaction between Dendritic Cells and CD8+ T Cells Is Needed to Stimulate Maximal T Cell Responses in the Absence of CD4+ T Cell Help J. Immunol., March 1, 2007; 178(5): 2844 - 2852. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. E. Blachere, H. K. Morris, D. Braun, H. Saklani, J. P. Di Santo, R. B. Darnell, and M. L. Albert IL-2 Is Required for the Activation of Memory CD8+ T Cells via Antigen Cross-Presentation. J. Immunol., June 15, 2006; 176(12): 7288 - 7300. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Lim, R. M. Sutherland, Y. Zhan, G. Deliyannis, L. E. Brown, and A. M. Lew Targeting CD45RB alters T cell migration and delays viral clearance Int. Immunol., February 1, 2006; 18(2): 291 - 300. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. P. Uldrich, N. Y. Crowe, K. Kyparissoudis, D. G. Pellicci, Y. Zhan, A. M. Lew, P. Bouillet, A. Strasser, M. J. Smyth, and D. I. Godfrey NKT Cell Stimulation with Glycolipid Antigen In Vivo: Costimulation-Dependent Expansion, Bim-Dependent Contraction, and Hyporesponsiveness to Further Antigenic Challenge J. Immunol., September 1, 2005; 175(5): 3092 - 3101. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Colgan, M. Asmal, B. Yu, and J. Luban Cyclophilin A-Deficient Mice Are Resistant to Immunosuppression by Cyclosporine J. Immunol., May 15, 2005; 174(10): 6030 - 6038. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Nakamura, K.-H. Sonoda, D. E. Faunce, J. Gumperz, T. Yamamura, S. Miyake, and J. Stein-Streilein CD4+ NKT Cells, But Not Conventional CD4+ T Cells, Are Required to Generate Efferent CD8+ T Regulatory Cells Following Antigen Inoculation in an Immune-Privileged Site J. Immunol., August 1, 2003; 171(3): 1266 - 1271. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Zhai, L. Meng, R. W. Busuttil, M. H. Sayegh, and J. W. Kupiec-Weglinski Activation of Alloreactive CD8+ T Cells Operates Via CD4-Dependent and CD4-Independent Mechanisms and Is CD154 Blockade Sensitive J. Immunol., March 15, 2003; 170(6): 3024 - 3028. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Shedlock, J. K. Whitmire, J. Tan, A. S. MacDonald, R. Ahmed, and H. Shen Role of CD4 T Cell Help and Costimulation in CD8 T Cell Responses During Listeria monocytogenes Infection J. Immunol., February 15, 2003; 170(4): 2053 - 2063. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Zhan, J. F. Purton, D. I. Godfrey, T. J. Cole, W. R. Heath, and A. M. Lew Without peripheral interference, thymic deletion is mediated in a cohort of double-positive cells without classical activation PNAS, February 4, 2003; 100(3): 1197 - 1202. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H.-M. Hu, H. Winter, J. Ma, M. Croft, W. J. Urba, and B. A. Fox CD28, TNF Receptor, and IL-12 Are Critical for CD4-Independent Cross-Priming of Therapeutic Antitumor CD8+ T Cells J. Immunol., November 1, 2002; 169(9): 4897 - 4904. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Zhai, L. Meng, F. Gao, R. W. Busuttil, and J. W. Kupiec-Weglinski Allograft Rejection by Primed/Memory CD8+ T Cells Is CD154 Blockade Resistant: Therapeutic Implications for Sensitized Transplant Recipients J. Immunol., October 15, 2002; 169(8): 4667 - 4673. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. E. Miller, J. Jones, T. Le, J. Whitmore, N. Boiani, B. Gliniak, and D. H. Lynch 4-1BB-Specific Monoclonal Antibody Promotes the Generation of Tumor-Specific Immune Responses by Direct Activation of CD8 T Cells in a CD40-Dependent Manner J. Immunol., August 15, 2002; 169(4): 1792 - 1800. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. M. Sutherland, B. S. McKenzie, Y. Zhan, A. J. Corbett, A. Fox-Marsh, H. M. Georgiou, L. C. Harrison, and A. M. Lew Anti-CD45RB antibody deters xenograft rejection by modulating T cell priming and homing Int. Immunol., August 1, 2002; 14(8): 953 - 962. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Zhai, X.-D. Shen, F. Gao, A. J. Coito, B. A. Wasowska, A. Salama, I. Schmitt, R. W. Busuttil, M. H. Sayegh, and J. W. Kupiec-Weglinski The CD154-CD40 T Cell Costimulation Pathway Is Required for Host Sensitization of CD8+ T Cells by Skin Grafts Via Direct Antigen Presentation J. Immunol., August 1, 2002; 169(3): 1270 - 1276. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-G. Yang, J. Qi, M.-G. Wang, and M. Sykes Donor-derived interferon gamma separates graft-versus-leukemia effects and graft-versus-host disease induced by donor CD8 T cells Blood, May 13, 2002; 99(11): 4207 - 4215. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Zhan, J. L. Brady, R. M. Sutherland, and A. M. Lew Without CD4 Help, CD8 Rejection of Pig Xenografts Requires CD28 Costimulation But Not Perforin Killing J. Immunol., December 1, 2001; 167(11): 6279 - 6285. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
