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1.
Kudo-Saito C Garnett CT Wansley EK Schlom J Hodge JW 《Cancer immunology, immunotherapy : CII》2007,56(12):1897-1910
Systemic IL-2 is currently employed in the therapy of several tumor types, but at the price of often severe toxicities. Local
vector mediated delivery of IL-2 at the tumor site may enhance local effector cell activity while reducing toxicity. To examine
this, a model using CEA-transgenic mice bearing established CEA expressing tumors was employed. The vaccine regimen was a
s.c. prime vaccination with recombinant vaccinia (rV) expressing transgenes for CEA and a triad of costimulatory molecules
(TRICOM) followed by i.t. boosting with rF-CEA/TRICOM. The addition of intratumoral (i.t.) delivery of IL-2 via a recombinant
fowlpox (rF) IL-2 vector greatly enhanced anti-tumor activity of a recombinant vaccine, resulting in complete tumor regression
in 70–80% of mice. The anti-tumor activity was shown to be dependent on CD8+ cells and NK1.1+. Cellular immune assays revealed that the addition of rF-IL-2 to the vaccination therapy enhanced CEA-specific tetramer+ cell numbers, cytokine release and CTL lysis of CEA+ targets. Moreover, tumor-bearing mice vaccinated with the CEA/TRICOM displayed an antigen cascade, i.e., CD8+ T cell responses to two other antigens expressed on the tumor and not the vaccine: wild-type p53 and endogenous retroviral
antigen gp70. Mice receiving rF-IL-2 during vaccination demonstrated higher avidity CEA-specific, as well as higher avidity
gp70-specific, CD8+ T cells when compared with mice vaccinated without rF-IL-2. These studies demonstrate for the first time that the level and
avidity of antigen specific CTL, as well as the therapeutic outcome can be improved with the use of i.t. rF-IL-2 with vaccine
regimens. 相似文献
2.
3.
Targeting interleukin-2 (IL-2) and/or agonist anti-CD40 antibody (Ab) into tumors represents an effective vaccination strategy
that avoids systemic toxicity and resolves treated-site tumors. Here, we examined IL-2 and/or anti-CD40 Ab-driven local versus
systemic T cell function and the installation of T cell memory. Single tumor studies showed that IL-2 induced a potent CD4+ and CD8+ T cell response that was limited to the draining lymph node and treated-site tumor, and lymph node tumor-specific CD8+ T cells did not upregulate CD44. A two-tumor model showed that while IL-2-treated-site tumors resolved, distal tumors continued
to grow, implying limited systemic immunity. In contrast, anti-CD40 Ab treatment with or without IL-2 expanded the systemic
T cell response to non-draining lymph nodes, and distal tumors resolved. Tumor-specific T cells in lymph nodes of anti-CD40
Ab ± IL-2-treated mice upregulated CD44, demonstrating activation and transition to effector/memory migratory cells. While
CD40-activated CD4+ T cells were not required for eradicating treated-site tumors, they, plus CD8+ T cells, were crucial for removing distal tumors. Rechallenge/depletion experiments showed that the effector/memory phase
required the presence of previously CD40/IL-2-activated CD4+ and CD8+ T cells to prevent recurrence. These novel findings show that different T cell effector mechanisms can operate for the eradication
of local treated-site tumors versus untreated distal tumors and that signaling through CD40 generates a whole of body, effector/memory
CD4+ and CD8+ T cell response that is amplified and prolonged via IL-2. Thus, successful immunotherapy needs to generate collaborating
CD4+ and CD8+ T cells for a complete long-term protective cure. 相似文献
4.
Suzanne P. M. Welten Anke Redeker Kees L. Franken Chris A. Benedict Hideo Yagita Felix M. Wensveen Jannie Borst Cornelis J. M. Melief René A. W. van Lier Klaas P. J. M. van Gisbergen Ramon Arens 《Journal of virology》2013,87(12):6851-6865
Cytomegaloviruses (CMVs) establish lifelong infections that are controlled in part by CD4+ and CD8+ T cells. To promote persistence, CMVs utilize multiple strategies to evade host immunity, including modulation of costimulatory molecules on infected antigen-presenting cells. In humans, CMV-specific memory T cells are characterized by the loss of CD27 expression, which suggests a critical role of the costimulatory receptor-ligand pair CD27-CD70 for the development of CMV-specific T cell immunity. In this study, the in vivo role of CD27-CD70 costimulation during mouse CMV infection was examined. During the acute phase of infection, the magnitudes of CMV-specific CD4+ and CD8+ T cell responses were decreased in mice with abrogated CD27-CD70 costimulation. Moreover, the accumulation of inflationary memory T cells during the persistent phase of infection and the ability to undergo secondary expansion required CD27-CD70 interactions. The downmodulation of CD27 expression, however, which occurs gradually and exclusively on inflationary memory T cells, is ligand independent. Furthermore, the IL-2 production in both noninflationary and inflationary CMV-specific T cells was dependent on CD27-CD70 costimulation. Collectively, these results highlight the importance of the CD27-CD70 costimulation pathway for the development of CMV-specific T cell immunity during acute and persistent infection. 相似文献
5.
Elkord E Burt DJ Drijfhout JW Hawkins RE Stern PL 《Cancer immunology, immunotherapy : CII》2008,57(6):833-847
Background The human 5T4 (h5T4) oncofoetal antigen is expressed by a wide variety of human carcinomas including colorectal, ovarian,
gastric and renal, but rarely on normal tissues. Its restricted expression on tumour tissues as well as its association with
tumour progression and bad prognosis has driven the development of a MVA-based vaccine (TroVax) which has been tested in several
early phase clinical trials and these studies have led to the start of a phase III trial in renal cell carcinoma patients.
We have recently shown that CD8+ T cells recognizing h5T4 can be generated in the absence of CD4+ T cells from peripheral blood lymphocytes of human healthy individuals.
Results We report the existence and expansion of human CD4+ T cells against h5T4 by stimulation with autologous monocyte-derived dendritic cells infected with a replication defective
adenovirus encoding the h5T4 cDNA (Ad-h5T4). The h5T4-specific T-cell responses in normal individuals are enhanced by initial
depletion of CD25+ cells (putative T regulatory cells) prior to the in vitro stimulation. We have identified a novel h5T4-derived 15-mer peptide
recognized by CD4+ T cells in HLA-DR4 positive healthy individuals. Interestingly, CD4+ T cells spontaneously recognizing a different 5T4 epitope restricted by HLA-DR were identified in tumour-infiltrating lymphocytes
isolated from a regressing renal cell carcinoma lung metastasis.
Conclusion Our data show that CD4+ T cells recognizing h5T4 can be expanded and detected in healthy individuals and a renal cell carcinoma patient. Such h5T4-specific
CD4+ T cells boosted or induced by vaccination could act to modulate both cell or antibody mediated anti-tumour responses.
This work was supported by Cancer Research UK. 相似文献
6.
Wölfl M Merker K Morbach H Van Gool SW Eyrich M Greenberg PD Schlegel PG 《Cancer immunology, immunotherapy : CII》2011,60(2):173-186
T cell-mediated immunotherapy against malignancies has been shown to be effective for certain types of cancer. However, ex vivo expansion of tumor-reactive T cells has been hindered by the low precursor frequency of such cells, often requiring multiple rounds of stimulation, resulting in full differentiation, loss of homing receptors and potential exhaustion of the expanded T cells. Here, we show that when using highly purified naïve CD8+ T cells, a single stimulation with peptide-pulsed, IFNγ/LPS-matured dendritic cells in combination with the sequential use of IL-21, IL-7 and IL-15 is sufficient for extensive expansion of antigen-specific T cells. Short-term expanded T cells were tumor-reactive, multifunctional and retained a central-memory-like phenotype (CD62L+, CCR7+, CD28+). The procedure is highly reproducible and robust as demonstrated for different healthy donors and for cancer patients. Such short-term tumor-antigen-primed, multifunctional T cells may therefore serve as a platform to target different malignancies accessible to immunotherapy. 相似文献
7.
8.
An impaired differentiation of naive CD4+ T cells towards Th2 cells may contribute to the chronic tissue-destructive T-cell activity in rheumatoid arthritis (RA). The differentiation of naive CD4+ T cells into memory Th2 cells by IL-7 in comparison with that by IL-4 was studied in RA patients and in healthy controls. Naive CD4+ T cells from peripheral blood were differentiated by CD3/CD28 costimulation in the absence of or in the presence of IL-7 and/or IL-4. The production of IFN-gamma and IL-4 was measured by ELISA and by single-cell FACS analysis to indicate Th1 and Th2 cell activity. CD3/CD28 costimulation and IL-7 were early inducers of IL-4 production, but primarily stimulated IFN-gamma production. In contrast, in short-term cultures exogenously added IL-4 did not prime for IL-4 production but suppressed IL-7-induced IFN-gamma production. Upon long-term stimulation of naive CD4+ T cells, IFN-gamma production was differentially regulated by IL-7 and IL-4, but IL-4 production was increased by both IL-7 and IL-4. IL-7 and IL-4 additively induced polarization towards a Th2 phenotype. This susceptibility of naive CD4+ T cells to become Th2 cells upon culture with IL-7 and IL-4 was increased in RA patients compared with that in healthy controls. These findings demonstrate that, in RA patients, differentiation of naive CD4+ T cells towards a Th2 phenotype by CD3/CD28 costimulation, IL-7 and IL-4 is not impaired. The perpetuation of arthritogenic T-cell activity in RA therefore seems not to be the result of intrinsic defects of naive CD4+ T cells to develop towards suppressive memory Th2 cells. 相似文献
9.
Thompson JA Srivastava MK Bosch JJ Clements VK Ksander BR Ostrand-Rosenberg S 《Cancer immunology, immunotherapy : CII》2008,57(3):389-398
Activation of tumor-reactive T lymphocytes is a promising approach for the prevention and treatment of patients with metastatic
cancers. Strategies that activate CD8+ T cells are particularly promising because of the cytotoxicity and specificity of CD8+ T cells for tumor cells. Optimal CD8+ T cell activity requires the co-activation of CD4+ T cells, which are critical for immune memory and protection against latent metastatic disease. Therefore, we are developing
“MHC II” vaccines that activate tumor-reactive CD4+ T cells. MHC II vaccines are MHC class I+ tumor cells that are transduced with costimulatory molecules and MHC II alleles syngeneic to the prospective recipient. Because
the vaccine cells do not express the MHC II-associated invariant chain (Ii), we hypothesized that they will present endogenously synthesized tumor peptides that are not presented by professional Ii+ antigen presenting cells (APC) and will therefore overcome tolerance to activate CD4+ T cells. We now report that MHC II vaccines prepared from human MCF10 mammary carcinoma cells are more efficient than Ii+ APC for priming and boosting Type 1 CD4+ T cells. MHC II vaccines consistently induce greater expansion of CD4+ T cells which secrete more IFNγ and they activate an overlapping, but distinct repertoire of CD4+ T cells as measured by T cell receptor Vβ usage, compared to Ii+ APC. Therefore, the absence of Ii facilitates a robust CD4+ T cell response that includes the presentation of peptides that are presented by traditional APC, as well as peptides that
are uniquely presented by the Ii− vaccine cells. 相似文献
10.
Pawlik A Ostanek L Brzosko I Brzosko M Masiuk M Machalinski B Gawronska-Szklarz B 《Arthritis research & therapy》2003,5(4):R210-R213
Clonal expansion of CD4+CD28- T cells is a characteristic finding in patients with rheumatoid arthritis (RA). Expanded CD4+ clonotypes are present in the peripheral blood, infiltrate into the joints, and persist for years. CD4+CD28- T cells are oligoclonal lymphocytes that are rare in healthy individuals but are found in high percentages in patients with
chronic inflammatory diseases. The size of the peripheral blood CD4+CD28- T-cell compartment was determined in 42 patients with RA and 24 healthy subjects by two-color FACS analysis. The frequency
of CD4+CD28- T cells was significantly higher in RA patients than in healthy subjects. Additionally, the number of these cells was significantly
higher in patients with extra-articular manifestations and advanced joint destruction than in patients with limited joint
manifestations. The results suggest that the frequency of CD4+CD28- T cells may be a marker correlating with extra-articular manifestations and joint involvement. 相似文献
11.
Søndergaard H Frederiksen KS Thygesen P Galsgaard ED Skak K Kristjansen PE Odum N Kragh M 《Cancer immunology, immunotherapy : CII》2007,56(9):1417-1428
Interleukin (IL)-21 is a recently discovered cytokine in early clinical development, which has shown anti-tumor activity in
various animal models. In the present study, we examine the anti-tumor activity of IL-21 protein therapy in two syngeneic
tumor models and its effect on the density of tumor infiltrating T cells. We treated mice bearing established subcutaneous
B16 melanomas or RenCa renal cell carcinomas with intraperitoneal (i.p.) or subcutaneous (s.c.) IL-21 protein therapy and
subsequently scored the densities of tumor infiltrating CD4+ and CD8+ T cells by immunohistochemistry. Whereas both routes of IL-21 administration significantly inhibited growth of small, established
RenCa and B16 tumors, only s.c. therapy significantly inhibited the growth of large, established tumors. We found a greater
bioavailability and significant drainage of IL-21 to regional lymph nodes following s.c. administration, which could account
for the apparent increase in anti-tumor activity. Specific depletion of CD8+ T cells with monoclonal antibodies completely abrogated the anti-tumor activity, whereas NK1.1+ cell depletion did not affect tumor growth. In accordance, both routes of IL-21 administration significantly increased the
density of tumor infiltrating CD8+ T cells in both B16 and RenCa tumors; and in the RenCa model s.c. administration of IL-21 led to a significantly higher density
of tumor infiltrating CD8+ T cells compared to i.p. administration. The densities of CD4+ T cells were unchanged following IL-21 treatments. Taken together, these data demonstrate that IL-21 protein has anti-tumor
activity in established syngeneic tumors, and we show that IL-21 therapy markedly increases the density of tumor infiltrating
CD8+ T cells. 相似文献
12.
Dowell AC Oldham KA Bhatt RI Lee SP Searle PF 《Cancer immunology, immunotherapy : CII》2012,61(5):615-628
4-1BB ligation co-stimulates T cell activation, and agonistic antibodies have entered clinical trials. Natural killer (NK)
cells also express 4-1BB following activation and are implicated in the anti-tumour efficacy of 4-1BB stimulation in mice;
however, the response of human NK cells to 4-1BB stimulation is not clearly defined. Stimulation of non-adherent PBMC with
OVCAR-3 cells expressing 4-1BB ligand (4-1BBL) or IL-12 resulted in preferential expansion of the NK cell population, while
the combination 4-1BBL + IL-12 was superior for the activation and proliferation of functional NK cells from healthy donors
and patients with renal cell or ovarian carcinoma, supporting long-term (21 day) NK cell proliferation. The expanded NK cells
are predominantly CD56bright, and we show that isolated CD56dimCD16+ NK cells can switch to a CD56brightCD16− phenotype and proliferate in response to 4-1BBL + IL-12. Whereas 4-1BB upregulation on NK cells in response to 4-1BBL required
‘help’ from other PBMC, it could be induced on isolated NK cells by IL-12, but only in the presence of target (OVCAR-3) cells.
Following primary stimulation with OVCAR-3 cells expressing 4-1BBL + IL-12 and subsequent resting until day 21, NK cells remained
predominantly CD56bright and retained both high cytotoxic capability against K562 targets and enhanced ability to produce IFNγ relative to NK cells
in PBMC. These data support the concept that NK cells could contribute to anti-tumour activity of 4-1BB agonists in humans
and suggest that combining 4-1BB-stimulation with IL-12 could be beneficial for ex vivo or in vivo expansion and activation
of NK cells for cancer immunotherapy. 相似文献
13.
Vyacheslav?A.?Shmarov Vladimir?V.?Malashchenko Maksim?E.?Meniailo Natalia?D.?Gazatova Natalia?M.?Todosenko Olga?B.?Melashchenko Andrei?G.?Goncharov Victor?I.?Seledtsov
CD3+ T lymphocytes were isolated by positive magnetic separation from the peripheral blood of healthy donors. In the absence of any additional activating stimuli, interleukin-7 (IL-7) was shown to augment the levels of T cells expressing CD25 activation marker both in CD4-positive and in CD4-negative effector memory (CD45RA-CD197-) T cell subsets, as well as in terminally differentiated (CD45RA+CD197-) T cells, without significantly affecting the activation status of naive (CD45RA+CD197+) and central memory (CD45RA-CD197+) T cells. In addition, IL-7 noticeably enhanced the production of IL-2, interferon-γ (IFN-γ), and IL-10, but not IL-4, in T cells. The direct effects of IL-7 on T cell activation induced in vitro by MACSiBead? particles coated with CD2, CD3, and CD28 antibodies (Abs) were also investigated. Upon cell activation, IL-7 significantly augmented the levels of CD25+ T cells in naive (CD45RA+CD197+), central memory (CD45RA-CD197+), and effector memory (CD45RA-CD197-) T-cell compartments. In addition, IL-7 facilitated activation of CD4- (but not CD4+) terminally differentiated effector (CD45RA+CD197-) T cells. Finally, IL-7 was found to upregulate the production of IL-2, IFN-γ, IL-4, and IL-10 by activated T cells. In conclusion, we speculate that IL-7 is capable of enhancing functional T cell activity without causing significant functional inbalance between various T cell subsets. 相似文献
14.
Albrecht J Frey M Teschner D Carbol A Theobald M Herr W Distler E 《Cancer immunology, immunotherapy : CII》2011,60(2):235-248
Clinical tumor remissions after adoptive T-cell therapy are frequently not durable due to limited survival and homing of transfused
tumor-reactive T cells, what can be mainly attributed to the long-term culture necessary for in vitro expansion. Here, we
introduce an approach allowing the reliable in vitro generation of leukemia-reactive cytotoxic T lymphocytes (CTLs) from naive
CD8+ T cells of healthy donors, leading to high cell numbers within a relatively short culture period. The protocol includes the
stimulation of purified CD45RA+ CD8+ T cells with primary acute myeloid leukemia blasts of patient origin in HLA-class I-matched allogeneic mixed lymphocyte-leukemia
cultures. The procedure allowed the isolation of a large diversity of HLA-A/-B/-C-restricted leukemia-reactive CTL clones
and oligoclonal lines. CTLs showed reactivity to either leukemia blasts exclusively, or to leukemia blasts as well as patient-derived
B lymphoblastoid-cell lines (LCLs). In contrast, LCLs of donor origin were not lysed. This reactivity pattern suggested that
CTLs recognized leukemia-associated antigens or hematopoietic minor histocompatibility antigens. Consistent with this hypothesis,
most CTLs did not react with patient-derived fibroblasts. The efficiency of the protocol could be further increased by addition
of interleukin-21 during primary in vitro stimulation. Most importantly, leukemia-reactive CTLs retained the expression of
early T-cell differentiation markers CD27, CD28, CD62L and CD127 for several weeks during culture. The effective in vitro
expansion of leukemia-reactive CD8+ CTLs from naive CD45RA+ precursors of healthy donors can accelerate the molecular definition of candidate leukemia antigens and might be of potential
use for the development of adoptive CTL therapy in leukemia. 相似文献
15.
Díaz-Montero CM El Naggar S Al Khami A El Naggar R Montero AJ Cole DJ Salem ML 《Cancer immunology, immunotherapy : CII》2008,57(4):563-572
During the antigen-dependant activation process several subsets CD8+ T cells appear with different phenotypic and functional characteristics. Recent studies indicate that the state of T cell differentiation radically affects their ability to effectively respond to tumor challenge, with early effector CD8+ T (CD62Lhigh) cells having better anti-tumor activity. Thus strategies aimed at optimizing the generation of such subpopulations could significantly enhance the effectiveness of adoptive cell therapy (ACT) for cancer. In this study, we show that priming of naïve CD8+ T cells in the presence of IL-12 selectively rescued early CD8+ CD62Lhi from activation induced cell death and resulted in the increased accumulation of this subset of CD8+ T cells. Furthermore, we demonstrated that IL-12 directly modulated the expression of CD62L on activated CD8+ T cells. When used for ACT, naïve CD8+ T cells primed in vitro in the presence of IL-12 showed superior anti-tumor activity toward B16 melanoma. Importantly, using the Pmel-1 model, priming pmel-1 cells in vitro with IL-12 reduced the state of functional tolerance associated with the non-mutated “self” tumor antigen gp100, as demonstrated by significant tumor responses in the absence of vaccination. Together, our results suggest that in vitro conditioning of naïve CD8+ T cells with IL-12 prior to ACT could significantly enhance their anti-tumor activity. 相似文献
16.
4-1BB is superior to CD28 costimulation for generating CD8+ cytotoxic lymphocytes for adoptive immunotherapy 总被引:2,自引:0,他引:2
Zhang H Snyder KM Suhoski MM Maus MV Kapoor V June CH Mackall CL 《Journal of immunology (Baltimore, Md. : 1950)》2007,179(7):4910-4918
Artificial APCs (aAPCs) genetically modified to express selective costimulatory molecules provide a reproducible, cost-effective, and convenient method for polyclonal and Ag-specific expansion of human T cells for adoptive immunotherapy. Among the variety of aAPCs that have been studied, acellular beads expressing anti-CD3/anti-CD28 efficiently expand CD4+ cells, but not CD8+ T cells. Cell-based aAPCs can effectively expand cytolytic CD8+ cells, but optimal costimulatory signals have not been defined. 4-1BB, a costimulatory molecule expressed by a minority of resting CD8+ T cells, is transiently up-regulated by all CD8+ T cells following activation. We compared expansion of human cytolytic CD8+ T cells using cell-based aAPCs providing costimulation via 4-1BB vs CD28. Whereas anti-CD3/anti-CD28 aAPCs mostly expand naive cells, anti-CD3/4-1BBL aAPCs preferentially expand memory cells, resulting in superior enrichment of Ag-reactive T cells which recognize previously primed Ags and efficient expansion of electronically sorted CD8+ populations reactive toward viral or self-Ags. Using HLA-A2-Fc fusion proteins linked to 4-1BBL aAPCs, 3-log expansion of Ag-specific CD8+ CTL was induced over 14 days, whereas similar Ag-specific CD8+ T cell expansion did not occur using HLA-A2-Fc/anti-CD28 aAPCs. Furthermore, when compared with cytolytic T cells expanded using CD28 costimulation, CTL expanded using 4-1BB costimulation mediate enhanced cytolytic capacity due, in part, to NKG2D up-regulation. These results demonstrate that 4-1BB costimulation is essential for expanding memory CD8+ T cells ex vivo and is superior to CD28 costimulation for generating Ag-specific products for adoptive cell therapy. 相似文献
17.
Bardos T Czipri M Vermes C Finnegan A Mikecz K Zhang J 《Arthritis research & therapy》2003,5(2):R106-R113
Accumulating evidence suggests that regulatory T cells play a crucial role in preventing autoimmunity. Recently, a naturally
occurring CD4+CD25+ T-cell subset that is anergic and also suppressive has been shown to suppress autoimmunity in several animal models. We used
proteoglycan-induced arthritis (PGIA) as a study model to investigate the role of the CD4+CD25+ regulatory T cells in autoimmune arthritis. There was no significant change in the percentage of CD4+CD25+ T cells during the immunization period when proteoglycan- or ovalbumin-immunized BALB/c and C57BL/6 mice were compared. An
adoptive transfer study showed that the CD4+CD25+ T cells did not protect severe combined immunodeficient mice from arthritis when they were cotransferred with splenocytes
from arthritic animals. Similarly, depletion of the CD4+CD25+ T cells did not enhance the onset of the disease or disease severity in severe combined immunodeficient mice. Moreover, CD28-deficient
mice, which have very few CD4+CD25+ T cells, were highly resistant to PGIA. These findings indicate that the CD4+CD25+ regulatory T cells may not play a critical role in controlling PGIA. 相似文献
18.
Molhoek KR McSkimming CC Olson WC Brautigan DL Slingluff CL 《Cancer immunology, immunotherapy : CII》2009,58(6):867-876
Targeted molecular therapies inhibit proliferation and survival of cancer cells but may also affect immune cells. We have
evaluated the effects of Sirolimus and Sorafenib on proliferation and survival of lymphoid cell subsets. Both drugs were cytotoxic
to CD4+CD25high T cells, and were growth inhibitory for CD4+ and CD8+ T cells. Cytotoxicity depended on CD3/CD28 stimulation and was detectable within 12 h, with 80–90% of CD4+CD25high cells killed by 72 h. Cell death was due to apoptosis, based on Annexin V and 7AAD staining. Addition of IL-2 prevented the
apoptotic response to Sirolimus, potentially accounting for reports that Sirolimus can enhance proliferation of CD4+CD25high cells. These results predict that Sirolimus or Sorafenib would reduce CD4+CD25high cells if administered prior to antigenic stimulation in an immunotherapy protocol. However, administration of IL-2 protects
CD4+CD25high T cells from cytotoxic effects of Sirolimus, a response that may be considered in design of therapeutic protocols. 相似文献
19.
Invariant or Type 1 NKT cells (iNKT cells) are a unique population of lymphocytes that share characteristics of T cells and
natural killer (NK) cells. Various studies have shown that positive costimulatory pathways such as the CD28 and CD40 pathways
can influence the expansion and cytokine production by iNKT cells. However, little is understood about the regulation of iNKT
cells by negative costimulatory pathways. Here, we show that in vivo activation with α-GalCer results in increased cytokine
production and expansion of iNKT cells in the absence of programmed cell death ligand-1 (PD-L1, B7-H1, and CD274). To study
whether PD-L1 deficiency on NKT cells would enhance antigen-specific T-cell responses, we utilized CD8+ OT-1 OVA transgenic T cells. α-GalCer enhanced the expansion and cytokine production of OT-1 CD8+ cells after adoptive transfer into wild-type recipients. However, this expansion was significantly enhanced when OT-1 CD8+ T cells were adoptively transferred into PD-L1−/− recipients. To extend these results to a tumor model, we used the B16 melanoma system. PD-L1−/− mice given dendritic cells loaded with antigen and α-GalCer had a significant reduction in tumor growth and this was associated
with increased trafficking of antigen-presenting cells and CD8+ T cells to the tumors. These data demonstrate that abrogating PDL1:PD-1 interactions during the activation of iNKT cells
amplifies an anti-tumor response when coupled with DC vaccination. 相似文献
20.
Yang S Hodge JW Grosenbach DW Schlom J 《Journal of immunology (Baltimore, Md. : 1950)》2005,175(6):3715-3723
The avidity of Ag-specific CTL is a critical determinant for clearing viral infection and eliminating tumor. Although previous studies have demonstrated that vaccines using enhanced costimulation will enhance the level and avidity of Ag-specific T cells from naive mice, there are conflicting data about the effects of vaccines using enhanced costimulation (vector or dendritic cell based) on the survival of memory T cells. In this study we have first extended previous observations that primary vaccination with a recombinant vaccinia virus (rV-) expressing a model Ag (LacZ) and a triad of T cell costimulatory molecules (B7-1, ICAM-1, and LFA-3 (designated TRICOM)) enhances the level and avidity of T cells from naive vaccinated C57BL/6 (Thy1.2) mice. Adoptive transfer of Thy1.1 memory CD8(+) T cells into naive Thy1.2 C57BL/6 mice was followed by booster vaccinations with a recombinant fowlpox (rF-)-expressing LacZ (rF-LacZ) or booster vaccinations with rF-LacZ/TRICOM. Analysis of levels of beta-galactosidase tetramer-positive T cells and functional assays (IFN-gamma expression and lytic activity) determined that booster vaccinations with rF-LacZ/TRICOM were superior to booster vaccinations with rF-LacZ in terms of both maintenance and enhanced avidity of memory CD8(+) T cells. Antitumor experiments using a self-Ag (carcinoembryonic Ag (CEA) vaccines in CEA transgenic mice bearing CEA-expressing tumors) also demonstrated that the use of booster vaccinations with vaccines bearing enhanced costimulatory capacity had superior antitumor effects. These studies thus have implications in the design of more effective vaccine strategies. 相似文献