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1.
Memory CD8+ T cells provide innate immune protection against Listeria monocytogenes in the absence of cognate antigen 总被引:6,自引:0,他引:6
Interferon (IFN)-gamma plays an important role in the innate immune response against intracellular bacterial pathogens. It is commonly thought that natural killer cells are the primary source of this cytokine that is involved in activating antibacterial effects in infected cells and polarizing CD4+ T cells toward the Th1 subset. However, here we show that both effector and memory CD8+ T cells have the potential to secrete IFN-gamma in response to interleukin (IL)-12 and IL-18 in the absence of cognate antigen. We demonstrate that memory CD8+ T cells specific for the ovalbumin protein secrete IFN-gamma rapidly after infection with wild-type Listeria monocytogenes (LM). Furthermore, small numbers of ovalbumin-specific, memory CD8+ T cells can reduce spleen and liver bacterial counts in IFN-gamma-deficient mice 3 d after LM infection. Up-regulation of the receptors for IL-12 and IL-18 provides a mechanism for the ability of memory CD8+ T cells to respond in this antigen nonspecific manner. Thus, CD8+ T cells play an important role in the innate immune response against intracellular pathogens by rapidly secreting IFN-gamma in response to IL-12 and IL-18. 相似文献
2.
Varadarajan N Julg B Yamanaka YJ Chen H Ogunniyi AO McAndrew E Porter LC Piechocka-Trocha A Hill BJ Douek DC Pereyra F Walker BD Love JC 《The Journal of clinical investigation》2011,121(11):4322-4331
CD8+ T cells are a key component of the adaptive immune response to viral infection. An inadequate CD8+ T cell response is thought to be partly responsible for the persistent chronic infection that arises following infection with HIV. It is therefore critical to identify ways to define what constitutes an adequate or inadequate response. IFN-γ production has been used as a measure of T cell function, but the relationship between cytokine production and the ability of a cell to lyse virus-infected cells is not clear. Moreover, the ability to assess multiple CD8+ T cell functions with single-cell resolution using freshly isolated blood samples, and subsequently to recover these cells for further functional analyses, has not been achieved. As described here, to address this need, we have developed a high-throughput, automated assay in 125-pl microwells to simultaneously evaluate the ability of thousands of individual CD8+ T cells from HIV-infected patients to mediate lysis and to produce cytokines. This concurrent, direct analysis enabled us to investigate the correlation between immediate cytotoxic activity and short-term cytokine secretion. The majority of in vivo primed, circulating HIV-specific CD8+ T cells were discordant for cytolysis and cytokine secretion, notably IFN-γ, when encountering cognate antigen presented on defined numbers of cells. Our approach should facilitate determination of signatures of functional variance among individual effector CD8+ T cells, including those from mucosal samples and those induced by vaccines. 相似文献
3.
Targeting T lymphocytes for immune monitoring and intervention in autoimmune diabetes 总被引:4,自引:0,他引:4
Recognition of a peptide-MHC complex by the T cell receptor (TCR) is a key interaction that initiates T lymphocyte activation or silencing during an immune response. Fluorochrome-labeled recombinant MHC class II-peptide reagents function as soluble mimetics of this interaction, bind to their specific TCR, and allow for detection of antigen-specific CD4+ T cells. These reagents are now under scrutiny for "immune staging" of patients at risk of type 1 diabetes, in an effort to diagnose islet autoimmunity early enough to block immune-mediated beta cell destruction. Several issues are currently being addressed to improve the performance of these T cell assays: enrichment steps for better sensitivity, multiplexing of several islet epitopes, simultaneous monitoring of CD4+ and CD8+ responses, detection of low avidity T cells, combination of quantitative (number of positive cells) and qualitative (cytokine secretion, naive/memory phenotype) readouts. CD4+ T cells are key effectors of autoimmunity, and these MHC class II peptide reagents, through their signaling properties, might also provide therapeutics to block the autoimmune process at its onset, analogous to the use of OKT3gammao1(AlaAla) anti-CD3 antibody but in an antigen-specific fashion. The aim of such therapeutics is to potentiate different physiological control mechanisms to restore immune tolerance. Mechanisms initiated by this pathway may be capable of triggering elimination of pathogenic T cells through antigen-specific apoptosis and anergy, combined with the induction of regulatory T cells with broad suppressive function. 相似文献
4.
CD4+CD25+ T cells protect against experimentally induced asthma and alter pulmonary dendritic cell phenotype and function 总被引:19,自引:0,他引:19
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Lewkowich IP Herman NS Schleifer KW Dance MP Chen BL Dienger KM Sproles AA Shah JS Köhl J Belkaid Y Wills-Karp M 《The Journal of experimental medicine》2005,202(11):1549-1561
The role of natural CD4+CD25+ regulatory T (T reg) cells in the control of allergic asthma remains poorly understood. We explore the impact of T reg cell depletion on the allergic response in mice susceptible (A/J) or comparatively resistant (C3H) to the development of allergen-induced airway hyperresponsiveness (AHR). In C3H mice, anti-CD25-mediated T reg cell depletion before house dust mite treatment increased several features of the allergic diathesis (AHR, eosinophilia, and IgE), which was concomitant with elevated T helper type 2 (Th2) cytokine production. In similarly T reg cell-depleted A/J mice, we observed a moderate increase in airway eosinophilia but no effects on AHR, IgE levels, or Th2 cytokine synthesis. As our experiments suggested that T reg cell depletion in C3H mice before sensitization was sufficient to enhance the allergic phenotype, we characterized dendritic cells (DCs) in T reg cell-depleted C3H mice. T reg cell-depleted mice had increased numbers of pulmonary myeloid DCs with elevated expression of major histocompatibility complex class II, CD80, and CD86. Moreover, DCs from T reg cell-depleted mice demonstrated an increased capacity to stimulate T cell proliferation and Th2 cytokine production, which was concomitant with reduced IL-12 expression. These data suggest that resistance to allergen-driven AHR is mediated in part by CD4+CD25+ T reg cell suppression of DC activation and that the absence of this regulatory pathway contributes to susceptibility. 相似文献
5.
Aruga E Tanigawa K Aruga A Arai H Smith JW Nickoloff BJ Nabel GJ Chang AE 《Journal of immunotherapy (Hagerstown, Md. : 1997)》2000,23(2):225-234
The authors examined cellular mechanisms involved in anti-tumor reactivity induced by the murine MT-9G1 mammary tumor line, which was transduced to secrete granulocyte macrophage-colony-stimulating factor (GM-CSF). Compared with the parental MT-901 tumor, MT-9G1 subcutaneous tumors elicited an influx of CD4+ cells and dendritic cells. Secondary in vitro activation of tumor-draining lymph node cells with anti-CD3 and interleukin-2 resulted in effector cells that can mediate regression of established pulmonary metastases after adoptive transfer. In vivo depletion of T-cell subsets showed that tumor regression required CD4+ tumor-draining lymph node cells rather than CD8+ cells. The activated CD4+ cells expressed CD95L and mediated lysis of CD95+ MT-901 tumor cells, which were major histocompatibility complex class II negative. The CD4+ cells also released GM-CSF in response to tumor stimulation. A Fas fusion protein inhibited tumor lysis and GM-CSF release by the CD4+ cells. These studies document an alternate pathway by which CD4+ immune cells may recognize major histocompatibility complex class II-deficient tumors in which CD95L-bearing T cells induced an anti-tumor response mediated via CD95L:CD95. 相似文献
6.
目的探讨重组人(rh)IL-11、rhG-CSF联合应用对小鼠脾脏T淋巴细胞数量和功能的影响及其机制。方法应用流式细胞仪对细胞因子处理后的各组T淋巴细胞和亚群、共刺激分子CD28以及抑制性T淋巴细胞(CD3+CD4-CD8-、CD8+CD28-、CD4+CD25+)的数量进行测定;应用MTT法检测各组T淋巴细胞的增殖能力、混合淋巴细胞反应;测定细胞内IL-4、IFN-γ的分泌情况。结果经rhG-CSF单独及rhIL-11、rhG-CSF联合处理淋巴细胞总数和T细胞亚群与对照组比较均下降(P<0.05),而联合处理组CD3+、CD4+、CD8+细胞下降较明显,与其它各组比较差异有统计学意义(P<0.01),CD4+/CD8+细胞的比值联合处理组亦低于其它各组;G-CSF组及联合处理组CD3+CD28+细胞比例与对照组比较下降(P<0.01),CD4+CD28+、CD8+CD28+细胞联合处理组虽较其它各组低,但各组间差异无统计学意义;CD3+CD4-CD8-和CD4+CD25+抑制性T淋巴细胞各组间均无明显差异,而联合处理组CD8+CD28-抑制性T淋巴细胞较其它各组增加(P<0.05);细胞因子动员后各组T淋巴细胞增殖能力、供鼠对异种抗原的反应能力均降低(P<0.05),而联合处理组比其它各组下降更明显;联合处理组、G-CSF组与对照组比较细胞内细胞因子IFN-γ水平下降、IL-4水平升高,联合处理组与G-CSF组比较差异无统计学意义,但IFN-γ/IL-4的比值联合组低于其它各组(P<0.05)。结论rhIL-11与rhG-CSF体内应用后可产生协同作用,通过对T淋巴细胞数量和功能的影响来诱导机体免疫耐受。 相似文献
7.
Elimination of CD4+ suppressor T cells from susceptible BALB/c mice releases CD8+ T lymphocytes to mediate protective immunity against Leishmania 总被引:9,自引:3,他引:9
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This study examined the capacity of BALB/c mice that had been depleted of T cell subpopulations to generate a protective immune response to Leishmania major. Thymectomized mice were depleted of either L3T4+ (CD4+) T lymphocytes, Ly2+ (CD8+) T lymphocytes, or both, by treatment with appropriate mAbs. It was found that susceptible mice were rendered resistant to Leishmania by an intravenous infusion of anti-L3T4 mAb. These mice generated an immune response that destroyed the parasite in the primary lesion and in visceral metastatic foci. CD4+ cell-depleted mice also acquired a capacity to mount a sustained delayed-type hypersensitivity (DTH) response to parasite antigens, indicating that DTH, per se, is not a disease-promoting mechanism in the susceptible murine host as has been suggested. Depleting BALB/c mice of CD8+, as well as CD4+ T cells, left them highly susceptible to Leishmania infection, thereby indicating that CD8+ lymphocytes are key protective cells. Our results can be interpreted as showing that the susceptibility of BALB/c mice is due to the generation of CD4+ cells that suppress either the generation or expression of CD8+ T cell-mediated antiLeishmania immunity. 相似文献
8.
Specific killing of cytotoxic T cells and antigen-presenting cells by CD4+ cytotoxic T cell clones. A novel potentially immunoregulatory T-T cell interaction in man 总被引:8,自引:1,他引:7
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Mycobacterial antigens not only stimulate Th cells that produce macrophage-activating factors, but also CD4+ and CD8+ CTL that lyse human macrophages. The mycobacterial recombinant 65-kD hsp was previously found to be an important target antigen for polyclonal CD4+ CTL. Because of the major role of 65-kD hsp in the immune response to mycobacterial as well as autoantigens, we have studied CTL activity to this protein at the clonal level. HLA-DR or HLA-DQ restricted, CD4+CD8- T cell clones that recognize different peptides of the M. leprae 65-kD hsp strongly lysed EBV-BLCL pulsed with specific but not irrelevant peptide. No bystander lysis of B cells, T cells, or tumor cells was seen. Target cell lysis could not be triggered by PMA + Ca2+ ionophore alone and depended on active metabolism. Interestingly, these CD4+ CTL also strongly lysed themselves and other HLA-class II compatible CD4+ (TCR-alpha/beta or -gamma/delta) or CD8+ CTL clones in the presence of peptide, suggesting that CTL are not actively protected from CTL-mediated lysis. Cold target competition experiments suggested that EBV-BLCL targets were more efficiently recognized than CD4+ CTL targets. These results demonstrate that hsp65 peptide-specific HLA class II-restricted CD4+ T cell clones display strong peptide-dependent cytolytic activity towards both APCs, and, unexpectedly, CD4+ and CD8+ CTL clones, including themselves. Since, in contrast to murine T cells human T cells express class II, CTL-mediated T cell killing may represent a novel immunoregulatory pathway in man. 相似文献
9.
T淋巴细胞在抗肿瘤的免疫反应中起着重要作用,而大部分肿瘤患者往往存在免疫功能低下。本研究通过对急性髓系白血病(AML)患者T淋巴细胞胞内细胞因子特性的研究,以了解AML患者在不同状态下T淋巴细胞的功能。18例不同状态下初诊AML患者和10例健康成人外周血中的T淋巴细胞在莫能霉素存在的情况下,体外经PMA和离子霉素(ionomycin)刺激后,分别进行CD4-FITC、CD8-FITC荧光单克隆抗体染色和IFNγ-PE、IL4-PE荧光单克隆体胞内染色,最后进行流式细胞仪分析。结果表明:初诊AML患者中CD4^+和CD8^+T淋巴细胞胞内IFNγ分泌水平均明显低于健康成人外周血T淋巴细胞,CD4^+和CD8^+T细胞胞内IL-4分泌水平与成人外周血细胞无显著差异。处于临床缓解状态的AML患者,CD8^+T淋巴细胞刺激后胞内产生IFNγ的量明显高于初诊AML患者(P〈0、05).但与健康成人无显著差异(P〉0、05)。复发的AML患者外周血中CD4^+T细胞和CD8^+T细胞刺激后胞内产生IFNγ量明显低于健康成人外周血T淋巴细胞以及处于完全缓解状态的AML患者CD8^+T淋巴细胞(P〈0、05).而IL-4的量明显高于健康成人和初诊AML患者CD4^+T细胞和CD8^+T细胞(p〈0.05)。结论:处于不同状态下的AML患者T细胞亚群分泌的细胞因子发生了改变,与之相应的是,初次诊断的AML患者外周血中CD4‘和CD8’T淋巴细胞刺激后Th1/Tcl细胞反应低下,Th2/Tc2细胞反应与健康成人T淋巴细胞无差异;完全缓解状态的AML患者T细胞Thl反应虽然仍低下,但Tcl反应明显增强,与健康成人无差异;复发的AML患者CD4^+和CD8^+T细胞Th2/Tc2样反应较Thl/Tcl样反应明显增强。 相似文献
10.
Manipulation of the cytokine microenvironment at the time of vaccination can influence immune responses to remote challenge, providing a strategy to study the molecular pathogenesis of respiratory syncytial virus (RSV) vaccine-enhanced disease in the mouse model. Although treatment with antibody against IL-4 or recombinant IL-12 (rIL-12) at the time of formalin-inactivated RSV vaccination induced a similar shift in the pattern of cytokine mRNA expression upon live virus challenge, anti-IL-4 treated mice had increased CD8+ cytotoxic T lymphocyte activity and reduced illness compared with rIL-12-treated mice. To define effector mechanisms responsible for these patterns, CD4+ and/or CD8+ T lymphocytes were selectively depleted in vivo at the time of RSV challenge. In rIL-12-treated mice, CD4+ lymphocytes made the largest contribution to IFN-gamma mRNA, RSV clearance, and illness, while in anti-IL-4 treated mice, CD8+ lymphocytes were the major effector. The effector responsible for virus clearance also mediated illness, suggesting that efficiency of virus clearance determined disease expression. These results demonstrate that the phenotype of effector cells involved in the immune response to virus challenge may be a more important determinant of disease than patterns of cytokine expression classically assigned to Th1 and Th2 lymphocytes. 相似文献
11.
De Giovanni C Nicoletti G Landuzzi L Rossi I Astolfi A Ricci C Di Carlo E Musiani P Forni G Fradelizi D Nanni P Lollini PL 《Gene therapy》2001,8(22):1698-1704
TS/A spontaneous mouse mammary adenocarcinoma cells were engineered to release interferon-gamma (IFN-gamma), a Th1 cytokine (TS/A-IFNgamma) and interleukin-13 (IL-13), a Th2 cytokine (TS/A-IL13). Mice bearing lung micrometastases induced by parental TS/A cells received repeated subcutaneous vaccinations with TS/A-IFN-gamma admixed with TS/A-IL13 engineered cells. This combined treatment cured up to 75% of mice, whereas vaccinations with either TS/A-IFNgamma or TS/A-IL13 alone cured only 20-40% of mice. Combined TS/A-IL13 and TS/A-IFNgamma therapeutic vaccinations elicited a reactive infiltrate of CD4+ and CD8+ lymphocytes in lung metastases and an increased production of IFN-gamma in the spleen and lung, suggesting a shift of the immune response toward the Th1 type. The type of infiltrating cells along with the lack of efficacy in T cell-deficient mice point to a major role of T cells. In conclusion, no antagonism but a synergistic and effective definitive cure stems from the combined vaccination with tumor cells engineered to release a Th1 and a Th2 cytokine. 相似文献
12.
B Hehmke E Salzsieder G B Matic R E Winkler M Tiess W Ramlow 《Therapeutic apheresis》2000,4(4):296-302
Intracellular cytokine staining and flow cytometry were used to investigate whether immunoadsorption (IA) of immunoglobulins alters intracytoplasmic cytokine production in CD4+ and CD8+ T cells from the blood of patients with refractory rheumatoid arthritis (n = 7), membrane proliferative glomerulonephritis (n = 1), and Goodpasture's syndrome (n = 1). Four patients (Group 1) showed severely depressed production of TNF-alpha, IL-2, IFN-gamma, and IL-4 by CD4+ and CD8+ T cells and responded to 3 IA sessions with significant increases in CD4+TNF-alpha+, CD4+IL-2+, and CD8+IL-2+ T cells. Also, a tendency toward increased percentage levels of CD4+ T cells producing IFN-gamma or IL-4 and of CD8+ T cells producing either TNF-alpha or IFN-gamma was seen, but due to the small number of patients investigated, these differences did not attain statistic significance. Group 2 (n = 5) showed unimpaired intracellular cytokine levels and responded to IA with a heterogeneous pattern of changes in TNF-alpha, IL-2, IFN-gamma, and IL-4 production, but these alterations were smaller than those in Group 1. The present findings indicate that the extracorporeal removal of immunoglobulins by anti-IgG or protein A adsorber columns has an impact on T cell immunity and suggest that modulating effects on cellular immune system function are involved in the mode of action of IA. 相似文献
13.
CD4+CD25+ T cells regulate virus-specific primary and memory CD8+ T cell responses 总被引:35,自引:0,他引:35
Suvas S Kumaraguru U Pack CD Lee S Rouse BT 《The Journal of experimental medicine》2003,198(6):889-901
Naturally occurring CD4+CD25+ regulatory T cells appear important to prevent activation of autoreactive T cells. This article demonstrates that the magnitude of a CD8+ T cell-mediated immune response to an acute viral infection is also subject to control by CD4+CD25+ T regulatory cells (Treg). Accordingly, if natural Treg were depleted with specific anti-CD25 antibody before infection with HSV, the resultant CD8+ T cell response to the immunodominant peptide SSIEFARL was significantly enhanced. This was shown by several in vitro measures of CD8+ T cell reactivity and by assays that directly determine CD8+ T cell function, such as proliferation and cytotoxicity in vivo. The enhanced responsiveness in CD25-depleted animals was between three- and fourfold with the effect evident both in the acute and memory phases of the immune response. Surprisingly, HSV infection resulted in enhanced Treg function with such cells able to suppress CD8+ T cell responses to both viral and unrelated antigens. Our results are discussed both in term of how viral infection might temporarily diminish immunity to other infectious agents and their application to vaccines. Thus, controlling suppressor effects at the time of vaccination could result in more effective immunity. 相似文献
14.
目的:探讨免疫抑制治疗(IST)前后淋巴细胞亚群变化与重型/极重型再生障碍性贫血(SAA/VSAA)患者疾病严重程度及IST后6个月血液学反应(HR)的关系。方法:对2009年12月至2011年10月本中心连续收治的94例行兔抗人胸腺细胞免疫球蛋白(r-ATG)+环孢素A(CsA)治疗的SAA/VSAA患者资料进行回顾性分析,对符合入组条件的26例患者IST前淋巴细胞亚群及细胞因子水平与疾病严重程度、IST前后淋巴细胞亚群及细胞因子变化与IST后6个月HR进行相关性分析。结果:IST前淋巴细胞比例(Lym%)和绝对值计数(Lym#)、各淋巴细胞亚群(包括CD3^+T细胞、CD3^+CD4^+T细胞、CD3^+CD8^+T细胞、CD3^-CD16^+/CD56^+NK细胞和CD19^+B细胞)比例(%)及绝对值(#)、细胞因子(包括IL-1、IL-2、IL-4、IL-6和TNF-α)水平,在SAA和VSAA两组间无统计学差异。IST后3个月和IST后6个月相比较,上述各参数水平无统计学差异。有效组IST后3及6个月Lym%、Lym#、CD3^+T细胞#、CD4^+T细胞%、CD4^+T细胞#、NK细胞%、B细胞#、IL-2水平显著低于治疗前,而无效组IST后3及6个月仅Lym%较治疗前显著降低。IST后3个月,有效组Lym#、CD3^+T细胞#及CD4^+T细胞#显著高于无效组。结论:IST前后淋巴细胞亚群变化所反映的免疫抑制程度,以及治疗后淋巴细胞亚群恢复所反映的免疫重建,可能影响造血恢复和早期血液学反应。免疫重建过程在IST后3月内较为显著。 相似文献
15.
The balance between proinflammatory and anti-inflammatory processes is of key importance in the reaction of the body to infection, injury, and surgical trauma. Drugs commonly used in anesthesia and intensive care may modulate immunological reactions by influencing intercellular communication through modification of cytokine response and fluctuation of peripheral immune cells such as natural killer (NK) cells, B cells, and T lymphocyte subpopulations (CD4+ and CD8+ cells). To examine the effects of general anesthesia with the hypnotic agent propofol and the opioid fentanyl, 30 patients undergoing minor elective orthopedic surgery were studied before and 20 min after application of the anesthetic drugs, but before the start of surgery. We found a significant enhancement of TNF-alpha and IL-1beta release in lipopolysaccharide (LPS)-stimulated whole blood cultures after induction of anesthesia. Similar results were observed with interferon-gamma (IFN-gamma) in cultures stimulated with phytohemagglutinin (PHA). Conversely, synthesis of the anti-inflammatory cytokine interleukin 10 (IL-10) decreased significantly in LPS-stimulated cultures. During general anesthesia, we found a decrease of circulating lymphocytes, characterized by a significant increase in the percentage of T lymphocytes in favor of CD4+ cells, increased B lymphocytes, and a significant decrease of NK cells. These data suggest that anesthesia with propofol and fentanyl promotes proinflammatory immune responses and influences peripheral lymphocyte composition in patients, which may subsequently affect pathophysiological processes during opioid-based anesthesia. 相似文献
16.
SLE患者T细胞亚群功能紊乱与Th1、Th2细胞因子偏移的研究 总被引:1,自引:1,他引:1
目的 :探讨系统性红斑狼疮 (SLE)患者细胞因子表达异常与细胞免疫功能紊乱的机制。方法 :用流式细胞仪根据直接免疫荧光法分别测定病例组与对照组T细胞表面标志CD3 ,CD4,CD8的表达情况。用微量反应板根据酶联免疫吸附测定法分别测定病例组与对照组血清IL - 2及IL - 6水平。结果 :SLE患者CD3 + CD4+ 细胞较正常对照组明显降低 (P <0 0 1) ,CD3 + CD8+ 细胞较正常对照组明显增加 (P <0 0 1) ,CD4+ T/CD8+ T细胞比例倒置 ;血清IL - 2水平较正常对照组明显降低 (P <0 0 1) ,而血清IL - 6水平较正常对照组明显增高 (P <0 0 5 )。结论 :SLE患者体内细胞免疫功能紊乱是介导免疫调节紊乱的主要因素 ,CD4+ T/CD8+ T细胞比例倒置 ,而CD4+ T细胞水平明显降低 ,其Th1,Th2细胞功能也表现明显偏移 ,以Th2细胞亢进为主 ,产生大量Th2细胞因子 ,介导免疫调节反应 ,致B淋巴细胞活跃产生大量自身抗体及免疫球蛋白。同时 ,CD8+ T细胞功能亢进 ,CTL细胞参与机体组织损伤 ,进一步导致免疫紊乱及免疫病理损伤加重 相似文献
17.
An unresolved issue in the field of T helper (Th) cell development relates to the findings that low doses of antigen promote Th2 cell development in vitro, whereas several classic in vivo studies suggest the opposite. Here we resolve this paradox by studying the early immune response in mice after infection with different doses of Leishmania major. We found that low parasite doses induced a Th2 response in C57BL/6 (B6) mice, whereas high doses induced a Th1 response. However, the Th2 response in low dose-infected mice was transient and the animals healed. The appearance of a Th1 response after low dose infection was dependent upon the concomitant activation of interferon gamma-producing CD8+ T cells. In the absence of CD8+ T cells, the Th2 response was maintained. However, either neutralization of interleukin (IL)-4 or administration of IL-12 promoted a Th1 response after low dose infection of CD8-deficient mice, indicating that the required role for CD8+ T cells was limited to modulation of CD4+ T cell responses. Thus, the discrepant results seen between in vivo and in vitro studies on the effects of antigen dose on Th cell differentiation may depend upon whether CD8+ T cells participate in the immune response. 相似文献
18.
Interleukin (IL) 4, in the absence of antigen stimulation, induces an anergy-like state in differentiated CD8+ TC1 cells: loss of IL-2 synthesis and autonomous proliferation but retention of cytotoxicity and synthesis of other cytokines 总被引:3,自引:2,他引:3
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《The Journal of experimental medicine》1995,182(5):1505-1515
Naive T cells in the periphery mainly secrete interleukin (IL) 2 upon activation. After stimulation in the presence of appropriate costimulators, both CD4+ and CD8+ T cells differentiate into effector cells secreting distinct T helper (Th) 1- and Th2-like cytokine patterns. Subsequent to differentiation, both CD4+ (Th1 and Th2) and CD8+ (TC1 and TC2) cells are stable and cannot be induced to differentiate into the opposite pattern or revert to the naive cytokine secretion pattern. We now show that IL-4 caused committed TC1 bulk populations or clones to lose the ability to synthesize IL-2. The cells retained the ability to secrete interferon (IFN) gamma, granulocyte/macrophage colony-stimulating factor, and tumor necrosis factor, did not synthesize any Th2 cytokines, and did not alter cell surface marker expression. IL-4 rapidly inhibited IL-2-synthesizing ability in the absence or presence of antigen-presenting cells, thus demonstrating that IL-4 acted directly on TC1 cells. The defect in IL-2 synthesis could not be reversed by subsequent stimulation with potent antigen-presenting cells in the presence of IL-2 and anti-IL-4, or with anti-CD3 plus anti-CD28 antibodies. Both IL-2+ and IL-2- TC1 cells were strongly cytotoxic toward allogeneic but not syngeneic targets. However, IL-2- TC1 cells were unable to proliferate unless exogenous IL- 2 was provided. TC1 cells that lose IL-2 synthesis but retain IFN-gamma synthesis and cytotoxicity may be similar to the "anergic" cells induced by stimulation of CD4+ or CD8+ cells in the absence of costimulators. These results suggest that during a mixed type 1/type 2 response in vivo, IL-4 may induce the IL-2+ TC1-->IL-2-TC1 conversion, and thus curtail the expansion of the TC1 response without impairing short-term effector function. 相似文献
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Virus-specific CD8+ cells can switch to interleukin 5 production and induce airway eosinophilia 总被引:11,自引:5,他引:11
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《The Journal of experimental medicine》1995,181(3):1229-1233
Virus infections of the lung are thought to predispose individuals to asthma, a disease characterized by eosinophil infiltration of the airways. CD8+ T cells are an important part of the host response to virus infection, however, they have no reported role in eosinophil recruitment. We developed a mouse model of virus peptide-stimulated CD8+ T cell immune responses in the lung. We found that bystander CD4+ T helper cell type 2 immune responses to ovalbumin switched the virus peptide-specific CD8+ T cells in the lung to interleukin (IL) 5 production. Furthermore, when such IL-5-producing CD8 T cells were challenged via the airways with virus peptide, a significant eosinophil infiltration was induced. In vitro studies indicated that IL-4 could switch the virus-specific CD8+ T cells to IL-5 production. These results could explain the link between virus infection and acute exacerbation of asthma and, perhaps more importantly, they indicate an IL-4-dependent mechanism that would impair CD8+ T cell responses and delay viral clearance from the host. 相似文献