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1.
4-1BBL(-/-) mice have a defect in recall CD8+ T cell responses to viruses, whereas CD4+ T cell responses to virus are unimpaired in these mice. In contrast, both CD4+ and CD8+ T cells respond to 4-1BB ligand (4-1BBL) in vitro. To clarify the role of 4-1BB/4-1BBL in CD4+ versus CD8+ T cell responses in vivo, we compared CD4 (OT-II) and CD8 (OT-I) TCR transgenic T cells responding to the same antigen in an in vivo adoptive transfer model in 4-1BBL(+/+) versus 4-1BBL(-/-) mice. During primary and secondary responses, expression of 4-1BB on in vivo-activated TCR transgenic T cells was earlier and more transient than previously observed in vitro, correlating with expression of the early activation antigen CD69 and preceding the transition to the CD44hi state. Although 4-1BB is expressed early in the primary response, there was no effect of 4-1BBL deficiency on initial CD8 T cell expansion and only a minor effect on initial CD4 T cell expansion. The major effect of 4-1BB/4-1BBL interaction is on the T cell recall response. This is due to effects of 4-1BBL on maintenance of T cell numbers at the end of the primary response with additional effects of 4-1BBL on secondary expansion of T cells.  相似文献   

2.
Co-stimulation of antigen-specific CD4 T cells by 4-1BB ligand   总被引:16,自引:0,他引:16  
4-1BB is a member of the TNF receptor family predominantly expressed on activated T cells, and binds an inducible ligand found on B cells, macrophages and dendritic cells. Whereas ligation of 4-1BB has been shown to enhance response of purified CD8 T cells to mitogens, and to augment NK activity and generation of cytotoxic T lymphocytes in vivo, there are little direct data on 4-1BB action during CD4 responses. Using pigeon cytochrome c-presenting fibroblast antigen-presenting cells transfected with 4-1BB ligand (4-1BBL), we show that engaging 4-1BB on naive CD4 cells promotes proliferation, cell cycle progression and IL-2 secretion, and suppresses cell death, all to a similar extent as B7-1 engagement of CD28. In addition, 4-1BBL synergizes with B7 and ICAM to enhance naive CD4 proliferation when antigen is limiting. 4-1BBL alone, and to a greater extent with B7, also augmented IL-2 secretion resting antigen-experienced CD4 cells, as typified by T helper clones, whereas short-term effector cells showed similar levels of proliferation and cytokine secretion regardless of whether 4-1BB was engaged. A major role in augmenting IFN-gamma, IL-4 or IL-5 was not demonstrated. Blocking studies with activated B cells presenting antigen showed that 4-1BB participates in promoting IL-2 production by resting CD4 cells, confirming that 4-1BBL can play a role in antigen-specific CD4 T cell responses.  相似文献   

3.
Immune-stimulating complexes (ISCOMS) are adjuvant vectors which are unusual in being able to prime both CD4(+) and CD8(+) T cells by parenteral and mucosal routes. However, their mode of action is unclear and to define better the cellular interactions involved we have studied the ability of ISCOMS containing ovalbumin (OVA) to prime TCR transgenic CD4(+) or CD8(+) T cells in vivo. Immunization with OVA ISCOMS caused activation and clonal expansion of CD4(+) and CD8(+) T cells in the T cell areas of the draining lymph nodes, followed by the migration of both CD4(+) and CD8(+) T cells into the B cell follicle. The T cells were primed to proliferate and secrete IFN-gamma after re-stimulation in vitro with the appropriate OVA peptide and CD8(+) T cell priming occurred in the absence of CD4(+) T cells. Increasing the number of dendritic cells (DC) in vivo with flt3 ligand augmented the expansion and activation of the OVA-specific T cells, particularly CD8(+) T cells. These studies indicate DC play a central role in the priming of both CD4(+) and CD8(+) T cells in vivo, and suggest that an ability to target DC may allow ISCOMS to be powerful vaccine vectors for stimulating protective immunity.  相似文献   

4.
4-1BB ligand (4-1BBL) expressed on antigen-presenting cells interacts with 4-1BB on activated T cells (especially CD8+ cells) and co-stimulates the latter to secrete cytokines and to proliferate. The role of 4-1BB-4-1BBL interaction was studied here in a model of colitis based on naive CD4+ T cell transfer to SCID mice, a disease model in which CD8 cells do not take part. We found that CD4+ T cells from 4-1BB-deficient mice, after transfer in SCID mice, proliferated more rapidly compared to wild-type CD4+ T cells. Mice reconstituted with naive CD4+ T cells from 4-1BB-deficient mice developed colitis, however, with a mixed Th1/Th2 response, in contrast to the Th1-type response in mice reconstituted with wild-type naive CD4+ T cells. Importantly, this altered cytokine response did not temper colitis severity. Although it has been reported previously that 4-1BB co-stimulation may contribute to regulatory T cell functioning, we found that CD4+CD25+ regulatory T cells from 4-1BB-deficient mice were perfectly able to prevent naive CD4+ T cell-induced colitis. In conclusion, our data provide evidence that 4-1BB-4-1BBL interaction modulates the effector CD4+ T cell-driven immune response and cytokine production in experimental colitis without affecting regulatory T cell function.  相似文献   

5.
Activation of T cells requires co-stimulation, in addition to signals through the antigen-receptor complex. Antigen encounter without adequate co-stimulation results in T-cell desensitization or anergy, a mechanism of peripheral tolerance and an apparent obstacle to cancer immunotherapy. One important co-stimulatory pathway involves CD28 engagement by CD80 or CD86. However, other ligand-receptor pairs can also provide co-stimulation and may have important functions modulating the immune response. Previous reports indicated that co-stimulation using 4-1BB ligand (4-1BBL) or agonistic anti-4-1BB antibodies could prolong T-cell responses, avoid activation-induced cell death and promote anti-tumour responses in mice. To further investigate the potential for cancer immunotherapy, we studied the effects of CD80/CD86 and 4-1BBL in repeated stimulation of human T cells and asked whether 4-1BBL might be capable of reversing anergy. We expressed CD80, CD86 and 4-1BBL in A549 lung carcinoma cells using adenovirus vectors and co-cultured these with human T cells stimulated with anti-CD3 antibody. Proliferation co-stimulated by CD80 or CD86 was transient; however, 4-1BBL-co-stimulated cultures continued to proliferate for up to 5 weeks, with repeated stimulation. Combined co-stimulation with CD80/CD86 and 4-1BBL also allowed continuous proliferation at a faster rate than either signal alone. Co-stimulation with 4-1BBL did not suppress expression of the inducible, inhibitory CD80/CD86R, CTLA-4. Significantly, we show that T cells that had become non-responsive to anti-CD3, either alone or together with CD80/CD86 co-stimulation, and thus were anergic, could be reactivated to proliferate when costimulated with 4-1BBL, either alone or combined with CD80/CD86.  相似文献   

6.
CD8(+)NKR-P1A (+)T cells preferentially accumulate in human liver.   总被引:6,自引:0,他引:6  
A unique subset of T cells that co-express NKR-P1, which is a lectin type of NK receptor and is thought to have a major role in triggering NK activity, has been identified. In mice, NK1.1 (mouse NKR-P1C)(+) T cells, called NKT cells, preferentially accumulate in the liver and bone marrow. They predominantly use invariant Valpha14 chain TCR and phenotypically are CD4(+)CD8(-) or CD4(-)CD8(-) T cells. In this study, we analyzed, phenotypically and functionally, the NKR-P1A (analogue of murine NKR-P1C)(+) T cells resident in the human liver. Here, we show that in complete contrast to the NKT cells in the mouse liver, the majority of NKR-P1A(+) T cells in the human liver are CD8(+) and their TCR repertoire is not skewed to Valpha24 TCR, the homologue of murine Valpha14 TCR. Almost all of the NKR-P1A(+) T cells in the human liver expressed CD69, suggesting that they were activated. Furthermore, the NKR-P1A(+) T cells in the human liver exhibited strong cytotoxicity against a variety of tumor cell lines including K562, Molt4 and some colonic adenocarcinoma cell lines.  相似文献   

7.
CD8(+)CD28(-) T cells have been characterized by oligoclonal expansions, impaired proliferative responses, but preserved cytotoxicity and reduced telomeres. To examine this subset further and define the underlying mechanisms of proliferation arrest, we investigated several features of this cell type compared with CD8(+)CD28(+) controls. We analyzed expression of various activation markers, thymidine incorporation upon activation, T-cell receptor (TCR) zeta-chain phosphorylation, cell cycle characteristics, and cell cycle related gene expression. Flow cytometry revealed higher expression of CD11b, CD29, CD57, and CD94, and lower expression of CD25 in CD8(+)CD28(-) compared with CD8(+)CD28(+) T cells. Sorted CD8(+)CD16(-)CD28(-) cells exhibited decreased phosphorylation of the TCR zeta-chain in three of four probands. Proliferation of these T cells was impaired, even when activated with mitogens that bypass TCR signaling. Cell cycle profiles demonstrated a lower percentage of cycling cells and significantly higher levels of cyclin dependent kinase inhibitor p16(INK4a) in the CD28(-) subset compared with the CD28(+) control. These observations suggest that expanded CD8(+)CD28(-) T cells in normal elderly individuals have reduced proliferation concomitant with increased p16(INK4a) expression. Defects in TCR signaling were associated with altered TCR zeta-chain phosphorylation.  相似文献   

8.
One of the consequences of HIV infection is a progressive loss of T cell functions, resulting in decreased cytokine secretion and proliferation and an increased sensitivity to apoptosis. Therefore, successful therapeutic vaccination approaches should aim at restoring the functionality of existing HIV-specific T cells, as well as to efficiently induce potent, HIV-specific T cells from na?ve T cells. In this study, we wanted to determine the stimulatory capacity of DCs coelectroporated with mRNA encoding for different costimulatory molecules of the TNFSF, together with HIV antigen-encoding mRNA. We show that DCs electroporated with 4-1BBL can enhance the proliferation, functionality, cytokine production, and survival of HIV-specific CD8(+) T cells. Furthermore, we are the first to show that a combination of 4-1BBL and CD40L overexpression on DCs dramatically enhances CD4(+) and CD8(+) T cell responses. Finally, we demonstrate that signaling through 4-1BB, but not through CD40, can alleviate the suppressive effect of Tregs on CD8(+) T cell proliferation. Thus, the combination of 4-1BBL and CD40L enhances HIV-specific CD8(+) T cell responses in a synergistic way, resulting in enhanced proliferation of CD4(+) and CD8(+) T cell subsets, an increased cytokine secretion, and a reduced sensitivity to Treg-mediated immune suppression.  相似文献   

9.
To characterize better the co-stimulatory activity of native B7-1 in the absence of other receptor/ligand interactions that might contribute to the response, B7-1 was purified by monoclonal antibody (mAb) affinity chromatography. Immobilization of purified B7-1 with anti-T cell receptor (TCR) mAb on cell-sized latex microspheres provided an effective stimulus for activation of both CD4+ and CD8+ T cells as measured by proliferation, development of effector function, and changes in motility and adhesion. The CD4+ T cell response was prolonged and resulted in efficient interleukin-2 production and clonal expansion. In contrast, CD8+ responses were transient. Proliferation and clonal expansion peaked on days 3 and 4, coincident with maximal expression of lytic effector function, and the cells then died. These results demonstrate that B7-1 mediated co-stimulation is sufficient for the induction of effector function in both helper and cytotoxic T cell precursors, but suggest that B7-1 co-stimulation is not sufficient to sustain helper-independent CD8+ CTL responses. When the dose responses of CD4+ and CD8+ T cells to B7-1 were compared, CD8+ T cells were found to require higher densities of B7-1 to attain an equivalent level of activation, suggesting that the level of expression of B7-1 by APC may influence the development of helper or CTL responses. Finally, in contrast to results obtained by others with B7-1 transfectants, purified B7-1 did not provide co-stimulation when presented on a surface separate from the TCR stimulus.  相似文献   

10.
目的 :探讨 4 1BB/ 4 1BBL协同刺激信号在CD4 和CD8 T细胞活化、增殖中的作用 ,并与CD2 8/B7信号作比较。方法 :用抗CD3单抗 (mAb)刺激人外周血单个核细胞 (PBMC)。用阻断型抗 4 1BBLmAb和抗CD80mAb ,分别阻断 4 1BB/ 4 1BBL和CD2 8/B7 1协同刺激信号。利用流式细胞术 (FCM)检测CD4 T细胞、CD8 T细胞的增殖率、CD8/CD4T细胞的比值变化和细胞分泌IFN γ的情况。结果 :用抗 4 1BBLmAb和抗CD80mAb阻断相应的协同刺激途径后 ,CD4 和CD8 T细胞的增殖和细胞分泌IFN γ的水平均明显下降。培养 8d,抗CD3mAb单独刺激组CD8/CD4T细胞的比值为 1.98± 0 .0 6 ;抗 4 1BBLmAb阻断组CD8/CD4T细胞的比值下降为 0 .96±0 .0 3;而在抗CD80mAb阻断组 ,其比值上升为 2 .6 9± 0 .16。结论 :4 1BB分子可在CD4 T细胞和CD8 T细胞的活化、增殖中提供协同刺激信号。 4 1BB分子所介导的协同刺激信号 ,在CD8 T细胞活化及增殖中发挥了更为重要的作用 ;而CD2 8分子所介导的协同刺激信号则更有利于CD4 T细胞的活化  相似文献   

11.
Zhao Y  Croft M 《Immunology letters》2012,141(2):220-226
CD8 T cells are strongly induced in response to certain strains of vaccinia virus (VACV) and the generation of this population is tightly regulated by two Tumor Necrosis Factor (TNF)/TNFR superfamily members, OX40 (CD134) and CD27. In this study, we examined the role of another member of the TNFR superfamily, 4-1BB (CD137, TNFRSF9), and its ligand (4-1BBL, CD137L, TNFSF9), that have been described to control the generation of memory CD8 T cell populations elicited by other viruses such as influenza. Expression of 4-1BB and 4-1BBL was observed in wild-type mice during the primary infection, but we found that both 4-1BB and 4-1BBL deficient mice generated normal numbers of VACV-specific effector CD8 T cells that produced IFN-γ and TNF. Additionally, CD8 T cells deficient in 4-1BB were able to expand and persist comparably to wild-type T cells in response to VACV infection. Furthermore, the knockout mice also showed no defect in development of VACV-specific CD8 memory T cell populations. Lastly, showing alternate control mechanisms were not active in the gene-deficient environments that masked any activity, blocking 4-1BB/4-1BBL interactions using neutralizing antibody also had no effect on the number of VACV-specific memory CD8 T cells induced. Thus, our data demonstrate that 4-1BB and 4-1BBL do not play a strong or dominant role in driving the generation of high frequencies of VACV-specific CD8 T cells.  相似文献   

12.
LIGHT-deficiency impairs CD8+ T cell expansion,but not effector function   总被引:2,自引:0,他引:2  
LIGHT, a newly identified member of the tumor necrosis factor (TNF) family, is expressed on activated T lymphocytes. To evaluate how LIGHT contributes to T cell functions, we generated LIGHT-deficient (LIGHT(-/-)) mice using gene targeting. Disruption of LIGHT significantly reduced CD8(+) T cell-cycle progression, leading to reduced proliferation to anti-CD3, anti-CD3/anti-CD28 or allogeneic stimulation, whereas proliferation of CD4(+) T cells remained unchanged. In contrast to the observed proliferative defects, isolated CD8(+) T cells from LIGHT(-/-) mice displayed normal cytotoxic effector function development when compared to wild-type CD8(+) T cells. Underlying a potential mechanism of reduced CD8(+) T cell proliferation, LIGHT(-/-) CD8(+) T cells displayed reduced surface levels of CD25 and a diminished ability to proliferate in response to exogenous IL-2. Furthermore, addition of IL-12 to LIGHT(-/-) CD8(+) T cell cultures could not ameliorate this proliferative defect. These results reveal a potential mechanism of action for LIGHT as a positive regulator of CD8(+) T cell expansion, but not lytic effector function development.  相似文献   

13.
The factors that influence the functionality of human CD4(+)CD25(+) regulatory T cells are not well understood. We sought to characterize the effects of dendritic cells (DCs) on the in vitro regulatory activity of CD4(+)CD25(+) T cells obtained from peripheral blood of healthy human donors. Flow cytometry showed that a higher proportion of CD4(+)CD25(+(High)) T cells expressed surface glucocorticoid-induced tumor necrosis factor receptor family-related protein (GITR) and CTL-associated antigen 4 than CD4(+)CD25(-) or CD4(+)CD25(+(Med-low)) T cells. Intracellular Foxp3 was equivalently expressed on CD4(+)CD25(+(All)), CD4(+)CD25(+(High)), CD4(+)CD25(+(Med-low)) and CD4(+)CD25(-) T cell populations, irrespective of GITR and CTL-associated antigen 4 expression. CD4(+)CD25(+) T cells were isolated and then cultured in vitro with CD4(+)CD25(-) responder T cells and stimulated with anti-CD3 antibodies, and immature dendritic cells (iDCs), mature dendritic cells (mDCs), PBMCs or PBMCs plus anti-CD28 antibodies to provide co-stimulation. In addition, secretion of the T(h)1 cytokine IFN-gamma, IL-2 and the immunoregulatory cytokines, IL-10 and transforming growth factor (TGF)-beta, were also assessed in these cultures. We found that iDCs and mDCs were capable of reversing the suppression of proliferation mediated by CD4(+)CD25(+) regulatory T cells. However, the reversal of suppression by DCs was not dependent upon the increase of IFN-gamma and IL-2 production or inhibition of IL-10 and/or TGF-beta production. Therefore, DCs are able to reverse the suppressive effect of regulatory T cells independent of cytokine production. These results suggest for the first time that human DCs possess unique abilities which allow them to influence the functions of regulatory T cells in order to provide fine-tuning in the regulation of T cell responses.  相似文献   

14.
At birth, virtually all peripheral CD8(+) T cells express the CD28 co-stimulatory molecule, but healthy human adults accumulate CD28(-)CD8(+) T cells that often express the CD57 marker. While these CD28(-) subpopulations are known to exert effector-type functions, the generation, maintenance and regulation of CD28(-) (CD57(+) or CD57(-)) subpopulations remain unresolved. Here, we compared the differentiation of CD8(+)CD28(bright)CD57(-) T cells purified from healthy adults or neonates and propagated in IL-2, alone or with IL-4. With IL-2 alone, CD8(+)CD28(bright)CD57(-) T cell cultures yielded a prevailing CD28(-) subpopulation. The few persisting CD28(dim) and the major CD28(-) cells were characterized by similar telomere shortening at the plateau phase of cell growth. Cultures from adults donors generated four final CD8(+) phenotypes: a major CD28(-)CD57(+), and three minor CD28(-)CD57(-), CD28(dim)CD57(-) and CD28(dim)CD57(dim). These four end-stage CD8(+) subpopulations displayed a fairly similar representation of TCR V(beta) genes. In cultures initiated with umbilical cord blood, virtually all the original CD8(+)CD28(bright) T cells lost expression of CD28, but none acquired CD57 with IL-2 alone. IL-4 impacted on the differentiation pathways of the CD8(+)CD28(bright)CD57(-) T cells: the addition of IL-4 led both the neonatal and the adult lymphocytes to keep their expression of CD28. Thus, CD8(+)CD28(bright)CD57(-) T cells can give rise to four end-stage subpopulations, the balance of which is controlled by both the cytokine environment, IL-4 in particular, and the proportions of naive and memory CD8(+)CD28(+) T cells.  相似文献   

15.
T cell and natural killer (NK) cell functions are regulated by triggering of activating and inhibitory cell surface receptors. Here, we have studied the expression profile and predicted inhibitory function of mouse "killer cell lectin-like receptor G1" (KLRG1) on CD8 T cells. KLRG1 was present on 1 - 3 % of adult splenic CD8 cells that expressed CD8alpha beta heterodimers as well as a polyclonal TCR Vbeta repertoire indicative of conventional CD8 cells. The majority of KLRG1(+) CD8 cells belonged to the memory pool as determined by extensive phenotypic marker analysis. Spontaneous IFN-gamma production by approximately 20 % of KLRG1(+) CD8 cells identified them as pro-inflammatory effector cells. In contrast to NK cells, Ly49 and KLRG1 expression on CD8cells was found to be mutually exclusive. Therefore, distinct programs regulate KLRG1 expression in CD8 and NK cells. Finally, we provide evidence that KLRG1 triggering interferes with TCRalpha beta-mediated Ca(++) mobilization and cytotoxicity, raising the possibility that KLRG1 functionally participates in down-regulation of CD8 T cell responses.  相似文献   

16.
4-1BB (CD137) is induced on activated CD4(+) and CD8(+) T cells and delivers a costimulatory signal upon binding the 4-1BB ligand (4-1BBL) expressed on antigen-presenting cells. Induction of 4-1BB is dependent on activation via the T-cell receptor (TCR) and possibly CD28. It was previously demonstrated that both an in vivo protein (pneumococcal surface protein A [PspA])- and polysaccharide (phosphorylcholine [PC] determinant of teichoic acid)-specific immunoglobulin (Ig) isotype response to Streptococcus pneumoniae was dependent on CD4(+) TCRalphabeta(+) T cells and B7-dependent costimulation through CD28. We thus postulated that 4-1BB costimulation would also play a role in regulating the in vivo anti-PspA and anti-PC response to S. pneumoniae. We demonstrate that mice genetically deficient in 4-1BBL elicit a markedly reduced IgM and IgG anti-PC but normal primary and secondary IgG anti-PspA responses to S. pneumoniae relative to those for wild-type mice. However, injection of an agonistic anti-4-1BB monoclonal antibody (MAb), while having no significant effect on the anti-PC response, strongly inhibits the primary anti-PspA response, the generation of PspA-specific memory, and germinal center formation but does not induce a lasting state of tolerance. In contrast, anti-4-1BB MAb has no effect on the anti-PspA response when injected only at the time of secondary immunization. Delay of the addition of anti-4-1BB leads to progressively less inhibition of the primary response up to day 8. This inhibition is independent of CD8(+) T cells and is associated with the expansion of CD4(+) T cells with an activated phenotype, which is partly dependent on B7-dependent costimulation. These data are the first to suggest a stimulatory role for endogenous 4-1BB-4-1BBL interactions during a humoral immune response to a pathogen and further underscore significant differences in costimulation requirements for an in vivo protein- versus polysaccharide-specific Ig isotype response to an extracellular bacterium.  相似文献   

17.
NRS1 is a murine squamous cell carcinoma that constitutively expresses the co-stimulatory molecule CD80 at a high level yet grows as a tumour in syngeneic C3H mice. We examined the effect of gene transfer of the 4-1BB ligand (4-1BBL) into NRS1 cells. Introduction of the 4-1BBL gene efficiently elicited anti-tumour immune responses in syngeneic mice which acquired specific immunity against wild-type tumour. T-cell depletion studies showed that CD8(+), but not CD4(+) T cells were essential for tumour eradication. Our results suggest that the transduced 4-1BBL is more effective than the spontaneously expressed CD80 for generation of primary anti-tumour CD8(+) T-cell responses. In addition to CD80 and CD86, the host-derived 4-1BBL is also involved in the secondary anti-tumour responses. This study indicates the complicated contribution of 4-1BBL, CD80 and CD86 on tumour and host cells in anti-tumour immune responses and a possible therapeutic application of 4-1BBL for human tumour vaccination and gene therapy.  相似文献   

18.
The chemotherapeutic agent methotrexate is widely used in the treatment of breast cancer. Although its mechanism-of-action has been defined, less is known about its interaction with Ag-specific T cell-mediated antitumor responses. Type 1 CD8 T cell-mediated immune responses (Tc1) are cytolytic, produce IFN-gamma and are associated with effective antitumor responses. Using a murine transgenic TCR tumor model, we show that single-dose-treatment with methotrexate enhanced CD8-mediated type 1 antitumor responses when administered three days prior to Tc1 effector cell transfer. Co-treatment with methotrexate not only enhanced donor Tc1 cell accumulation and persistence at sites of primary tumor growth, but also promoted elevated levels of activated CD25(+) expressing donor TIL cells. This correlated with a marked decrease in the appearance of endogenous differentiated (CD44(High)) CD3/CD8/CD49b and CD3/CD4/CD49b tumor-infiltrating effector T cells at both early (Days 1-8) and late (Days 12-20) stages following treatment when compared to that of corresponding groups receiving either MTX or Tc1 cell transfer alone. Moreover, such cellular response kinetics appeared to further correlate with the down-regulation of endogenous CD4/CD44(High)/CD49b effector T cells producing IL-10 and delays in tumor growth in vivo. This suggested that Ag-specific Tc1 cell transfer, in combination with chemotherapy, can enhance antitumor responses by modulating select CD49b-expressing T effector/memory cell subpopulations involved in homeostasis and immune tolerance within the tumor environment. These studies offer insight into mechanisms that enhance T cell-based immunotherapy in cancer. Supplementary materials are available for this article. Go to the publisher's online edition of Immunological Investigations for the following free supplemental resource(s): Addendum 1.  相似文献   

19.
To determine the effect of thymic stromal cells on the functional maturation of CD4 single-positive (SP) thymocytes, the functional status of isolated CD4 SP thymocyte subgroups was investigated by means of cell proliferation and cytokine production in response to concanavalin A (Con A) prior and after co-culturing with a murine thymic epithelial cell line (MTEC1). Mouse medullary CD4 SP thymocytes were phenotypically divided into seven discrete subgroups predicted to reflect the maturation pathway from newly emerging CD4 SP thymocytes to terminally differentiated cells. For functional analysis, six major subgroups (6C10(+)CD69(+), 6C10(-)CD69(+), 6C10(-)CD69(-)3G11(+)Qa-2(-), 6C10(-)CD69(-)3G11(+)Qa-2(+), 6C10(-)CD69(-)3G11(-)Qa-2(-) and 6C10(-)CD69(-)3G11(-)Qa-2(+)) cells were isolated and their functional status in response to Con A stimulation assessed. A functional hierarchy is revealed among these subgroups, consistent with their phenotypic maturation status, which may imply that these cells undergo a functional maturation process within thymic medulla. The function of cytokine production by CD4 SP thymocytes is acquired in a stepwise manner from a low to high level and characterized by T(h)0-type cytokines in the main stream of differentiation pathway. However, a minor subgroup that appeared at the late stage as 3G11(-)6C10(-) cells was biased to produce T(h)2-type cytokines. Nevertheless, the functional capacity of the final two Qa-2(+) subgroups of CD4 SP thymocytes was still significantly lower than that of spleen CD4(+) T cells. After co-cultivation with MTEC1 cells, four subgroups of TCRalphabeta(+)CD4(+)CD8(-) thymocytes exhibited significantly higher levels of proliferation capability and modulation in cytokine production capability. However, co-culturing with MTEC1 cells did not change the pattern of T(h)0- or T(h)2-like cytokine production by respectively medullary CD4 SP thymocyte subgroups nor could MTEC1 induce CD4 SP thymocytes to secrete T(h)1-type cytokines. The results suggest that MTEC1 can regulate the functional status of these thymocyte subgroups.  相似文献   

20.
We present a cross-sectional analysis of the maturation and migratory properties of the memory CD8(+) T cell compartment, in relation to the severity of heart disease in individuals with chronic Trypanosoma cruzi infection removed from endemic areas for longer than 20 years. Subjects with none or mild heart involvement were more likely to mount T. cruzi-specific memory IFN-gamma responses than subjects with more advanced cardiac disease, and the T. cruzi-specific CD8(+) T cell population was enriched in early-differentiated (CD27(+)CD28(+)) cells in responding individuals. In contrast, the frequency of CD27(+)CD28(+)CD8(+) T cells in the total memory CD8(+) T cell population decreases, as disease becomes more severe, while the proportion of fully differentiated memory (CD27(-)CD28(-)) CD8(+) T cells increases. The analysis of CCR7 expression revealed a significant increase in total effector/memory CD8(+) T cells (CD45RA(-)CCR7(-)) in subjects with mild heart disease as compared with uninfected controls. Altogether, these results are consistent with the hypothesis of a gradual clonal exhaustion in the CD8(+) T cell population, perhaps as a result of continuous antigenic stimulation by persistent parasites.  相似文献   

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