Signaling via CD28 costimulates lymphokine production,but does not reverse unresponsiveness to interleukin-2 in anti-CD3 triggered Th1 cells

Previously, it has been described that the ability of murine T_h1 cells to proliferate in response to exogenous interleukin (IL)-2 is blocked when these cells are exposed to immobilized anti-CD3 antibodies. In the present study we examined whether simultaneous triggering of the T cell antigen CD28 can prevent the induction of unresponsiveness to IL-2 in T_h1 cells. We report that costimulation of T_h1 cells with anti-CD28 monoclonal antibodies (mAb) did not overcome unresponsiveness to IL-2 induced by various amounts of immobilized anti-CD3 antibodies. However, stimulation with anti-CD28 mAb strongly augmented IL-2 and interferon-γ production in anti-CD3-exposed T_h1 cells. Thus, despite the fact that anti-CD28 mAb is a potent costimulus for lymphokine production, signaling through CD28 does not seem to be sufficient to trigger proliferation in T_h1 cells activated via the T cell receptor. These data suggest the existence of at least three signals to trigger T_h1 cell activation. The first is mediated by ligation of the T cell receptor. One cosignal, delivered by the CD28 molecule, leads to IL-2 production. A third, still undefined, signal is required for proliferation in response to IL-2.     

Ligation of either CD2 or CD28 rescues CD4+ T cells from HIV-gp120-induced apoptosis

Temporal or quantitative imbalance in signals delivered to T cells via T cell antigen receptor (TCR), the CD4 co-receptor, and accessory molecules can lead to anergy, apoptosis, or both. This has been observed following ligation of CD4 by HIV gp120 prior to TCR occupancy. The ability of molecules such as CD2 and CD28, interacting with their ligands LFA-3 and B7, to provide signals that protect T cells from the induction of anergy, has been reported. Here, we demonstrate that ligation of CD2 and CD28 in conjunction with TCR occupancy rescue T cells that have been programmed for apoptotic death by prior CD4 ligation to gp120. This appears to be the result of augmented interleukin-2 and interleukin-4 release by the T cells following these molecular interactions. In conclusion, our results suggest that an impairment of antigen-presenting accessory cell functions could favor gp120-mediated apoptosis in HIV-uninfected cells.     

Differences in responsiveness to CD3 stimulation between naive and memory CD4+ T cells cannot be overcome by CD28 costimulation

Activation of naive CD4⁺ T cells is essential for the induction of primary immune responses. However, this subset is less responsive to signaling via T cell receptor/CD3 (TcR/CD3) complex than memory CD4⁺ cells. For mitogenic activation of T cells, in addition to triggering of the TcR/CD3 complex, costimulatory signals are required that can be generated by surface structures present on the antigen-presenting cells. We investigated here whether differences in responsiveness to TcR/CD3 stimulation of naive and memory cells can be overcome by the costimulatory pathway B7/CD28. Using a B7-dependent system we show that even in the presence of optimal CD28 costimulation, CD4⁺ naive cells still have more stringent TcR/CD3 activation requirements than memory cells. Furthermore, titration of the B7 signal revealed that for activation of naive CD4⁺ cells a higher level of cross-linking of CD28 molecules is required than for memory cells. Thus, our results show that at least two signals are required for activation of both CD4⁺ memory and naive cells, but that for activation of naive cells higher cross-linking of both CD3 and CD28 molecules is necessary.     

急性冠脉综合征患者外周血CD4+CD28-T细胞与白细胞介素-6和C-反应蛋白的相关性研究

目的 检测急性冠脉综合征(ACS)患者外周血中CD4+ CD28-T细胞与IL-6和C-反应蛋白(CRP)相关性.方法 选取43例ACS患者,40例稳定性心绞痛(SAP),选取40例健康人作为正常对照.采用流式细胞分析仪测定CD4+ CD28-T细胞;IL-6和CRP水平分别采用ELISA法和特种蛋白分析仪进行测定.结果 ACS组患者的CD4+ CD28-T细胞数量和IL-6和CRP水平均显著高于SAP组(P＜0.001)或正常对照组(P＜0.001),而且ACS患者CD4+ CD28-T细胞与IL-6(r=0.79,P＜0.001)和CRP(r=0.50,P＜0.001)具有相关性.结论 ACS患者CD4+ CD28-T细胞数量的增高与IL-6和CRP高度相关,可能参与冠心病的病程进展.     

DNA甲基化在急性冠脉综合征患者CD4+CD28-T细胞CD28表达缺失中的作用

目的 通过研究急性冠脉综合征(acute coronary syndrome,ACS)患者外周血CD4+T细胞CD28 mRNA水平和CD28基因启动子调节序列的甲基化状态,旨在探讨DNA甲基化在ACS患者CD4+CD28-T细胞CD28表达缺失中的作用.方法 免疫磁珠分离CD4+T细胞经逆转录后,实时定量PCR(real time-PCR)技术检测CD4+T细胞CD28mRNA的表达水平,亚硫酸氢钠测序检测CD28基因启动子调节序列的甲基化状态.结果 与正常对照组相比,ACS患者CD4+T细胞CD28mRNA表达水平显著减低,差异具有统计学意义[正常对照组比ACS组:(1.066±0.162)比(0.401±0.069),P<0.05].CD28基因启动子区域的甲基化水平显著增高,差异有统计学意义[正常对照组比ACS组:(24.47±3.17)%比(43.33±1.52)%,P<0.05].CD28基因启动子区域DNA甲基化水平与CD28mRNA表达水平呈显著负相关(P=0.01,r=-0.579).结论 ACS患者CD4+T细胞CD28基因启动子区域高甲基化调控了CD28基因转录抑制.DNA甲基化参与了CD4+CD28-T细胞的形成.     

Human naive CD4 T cells produce interleukin-4 at priming and acquire a Th2 phenotype upon repetitive stimulations in neutral conditions

The maturation of naive CD4 T cells into interleukin (IL)-4-producing effectors was shown to require the presence of IL-4 at priming, the cellular origin of which remains unclear. We demonstrate here that naive T cells themselves release IL-4 at very low levels that are nevertheless sufficient to promote their development into Th2-like cells. This conclusion is based on three observations: (1) highly purified human naive CD4T cells, of neonatal or adult origin, develop into Th2 effectors upon repetitive cycles of stimulation with anti-CD3 monoclonal antibody (mAb) cross-linked to CD32-B7 transfected L fibroblasts followed by IL-2 expansion; (2) IL-4 protein is readily detectable in the concentrated supernatant fluids of priming cultures performed in the presence of anti-IL-4 receptor mAb; and (3) addition of anti-IL-4 or anti-IL-4 receptor mAb at priming markedly inhibits the acquisition of IL-4- and IL-5-producing capacity while enhancing that of interferon-γ.     

Development of human Th1 and Th2 cytokine responses: The cytokine production profile of T cells is dictated by the primary in vitro stimulus

Regulation of interleukin (IL)-4 production, but not IL-2 production, was found to be quite different in either freshly isolated T cells or T cell clones. Both fresh T cells and T helper 2-like clones produced IL-4 when stimulated with anti-CD2 in combination with anti-CD28. However, whereas T cell clones showed enhanced IL-4 production when phorbol 12-myristate 13-acetate (PMA) was used in addition to anti-CD2 and anti-CD28, IL-4 production by fresh T cells was inhibited by the presence of PMA. Prestimulation of fresh T cells led to the following observations: (a) activation in the absence of PMA led to a reversal of the PMA effect and (b) within 2 days these cells resembled T cell clones in that IL-4 production was no longer inhibited by PMA. When prestimulation was carried out in the presence of PMA, the inhibition of IL-4 production seemed irreversible. Removal of PMA after 3 days did not lead to renewed capability of IL-4 production, whereas IL-2 production was unimpaired. Our data show that the capacity of cultured T cells to produce IL-4 is determined and fixed during the first 2-3 days of stimulation.     

多发性骨髓瘤患者外周血CD4~+CD25~+和CD8~+CD28~-调节性T细胞研究

目的:探讨CD4~+CD25~+和CD8~+CD28~-调节性T细胞(Tregs)在多发性骨髓瘤(MM)患者外周血中的变化及意义.方法:采用流式细胞术检测38例MM患者及20例健康对照外周血CD4~+CD25~+和CD8~+CD28~-Tregs水平.分别采用溴甲酚绿法、透射免疫比浊法测定患者血清白蛋白(Alb)、β2-微球蛋白(β2-MG).结果:初诊MM患者外周血CD4~+CD25~(+/high)、CD4~+CD25~(high)CD127~(low)及CD8~+CD28~-Tregs比率均明显升高;CD4~+CD25~(+/high)和CD4~+CD25~)(high)CD127~(low)Tregs比率在各临床分期均较对照组升高,随分期增高呈现增加趋势,且CD4~+CD25~(high)和CD4~+CD25~(high)CD127~(low)Tregs在Ⅲ期患者显著高于Ⅰ期患者;CD8~+CD28~(-Tregs)在Ⅱ、Ⅲ期显著高于正常对照,且Ⅱ期高于Ⅰ期,Ⅲ期高于Ⅱ期,逐期递增,而在Ⅰ期与对照组比较无显著差异;CD4~+CD25~(+/high)和CD4~+CD25~(high)CD127~(low)Tregs比率在进展期和稳定期均较对照组升高,但两期之间比较无明显差异,而CD8~+CD28~-Tregs在进展期高于稳定期及对照组,稳定期和对照组间比较无明显差异;CD4~+CD25~(high)Tregs和CD4~+CD25~(high)CD127~(low)Tregs比率与Alb水平均呈负相关.结论:MM患者体内存在CD4~+CD25~+Tregs和CD8~+ CD28~-Tregs异常增加,可能是MM免疫逃逸的一个重要机制,这些变化同临床分期、病情进展及预后存在一定程度相关性.     

CD4+CD28-T细胞在急性冠脉综合征中的作用研究进展

近年来,在急性冠脉综合征(ACS)患者的粥样斑块中和外周血中发现一种不寻常的细胞,即CD4+CD28T淋巴细胞.该细胞以分泌Thl型细胞因子为主,具有大量扩增和寿命长的特征,且具有细胞毒性T细胞(CTL)的功能.这种T细胞亚群在斑块中的堆积引起了斑块的不稳定,参与ACS的发生.因而对该细胞的研究将为ACS的预防和治疗提供新的途径.     

A co-stimulatory role for CD28 in the activation of CD4+ T lymphocytes by staphylococcal enterotoxin B.

In this study we investigated the differential effect of the co-stimulatory receptor ligand molecules CD2/LFA-3, LFA-1/ICAM-1, and CD28/B7 on microbial superantigen mediated activation of CD4+ T cells. Highly purified CD4+ T cells, depleted of antigen presenting cells (APCs), do not proliferate in response to the superantigen, staphylococcal enterotoxin B (SEB). However, CD4+ T cells do respond to SEB in the presence of the LFA-3, ICAM-1, and B7 positive erythroleukemic cell line K562, murine L cells, human B7 transfected L cells or CD28 mAb. The K562 plus SEB induced response can be inhibited by combinations of mAbs to CD2 and LFA-1, and to LFA-3, ICAM-1, and B7. Addition of CD28 mAb to the CD2 and LFA-1 inhibited cultures could restore the response. Furthermore, soluble CD28 mAb alone is able to synergize with SEB to induce a proliferative CD4+ T cell response. CD4+ T cells depleted of APCs could also be activated by a pool of four mAbs directed to the V beta 5, V beta 6, V beta 8, and V beta 12 region of the TCR when a co-stimulatory signal was provided by the CD28 mAb, while the V beta mAbs alone or in combination are unable to activate CD4+ T cells in the absence of APCs. In contrast, addition of soluble mAbs to CD2 and LFA-1 molecules failed to co-stimulate SEB activated CD4+ T lymphocytes. The kinetics of the different modes of activation are distinct. SEB induced proliferation is most efficient in the presence of autologous APCs with maximal proliferation at a log4 lower SEB concentration than when CD28 mAbs were used. SEB plus K562 activation peaks on day 7, while SEB plus CD28 mAb induced proliferative responses do not peak until day 9. Thus, superantigen mediated activation of CD4+ T cells requires co-stimulatory signals, among which CD28 has distinct and unique effects.     

伴颈动脉粥样硬化脑梗患者CD4+CD28null T细胞CD158j表达和ERK磷酸化水平的关系

Objective To investigate the relationship between CD158j expression and phosphorylated ERK (p-ERK) in CD4+ CD28null T cells in cerebral infarction (CI) patients- with carotid atherosclerosis and its effects on carotid atherosclerotic plaque stability. Methods Percentage of peripheral CD4+ CD28null and the expression of CD158j and perform on CD4+ CD28null cells was analyzed with flow cytometry in 106 CI patients with carotid atherosclerosis, 33 CI patients with normal carotid arteries and in 50 normal controls, respectively; p-ERK expression was assayed with flow cytometry in 36 CI patients with unstable plaque, and serum IFN-γ was detected with ELISA. The intima-media thickness (IMT) of bilateral carotid arteries in all subjects was confirmed by the colour Doppler ultrasonograph imagingResults Percentage of the CD4+ CD28null T cells, expression of CD158j and perform on CD4+ CD28null T cells and the serum IFN-γ levels was dramatically higher in CI patients than that in normal controls, respectively (all P <0.01), which was decreased in an order of CI patients with patients with unstable plaque, stable plaque, carotid artery IMT and with normal carotid artery. A strong positive correlation was observed between the CD158j expression and degree of p-ERK in CI patients with unstable plaque (P < 0. 01). Conclusion CD4+ CD28null T cells were significantly increased in CI patients with carotid atherosclerosis. CD158j might up-regulate p-ERK expression and induce the proliferation of the CD4+ CD28nullT cells; consequently, higher cytokine production such as IFN-γ produced by CD4+ CD28null T cells may cause the formation of unstable plaque.     

伴颈动脉粥样硬化脑梗患者CD4+CD28null T细胞CD158j表达和ERK磷酸化水平的关系

Objective To investigate the relationship between CD158j expression and phosphorylated ERK (p-ERK) in CD4+ CD28null T cells in cerebral infarction (CI) patients- with carotid atherosclerosis and its effects on carotid atherosclerotic plaque stability. Methods Percentage of peripheral CD4+ CD28null and the expression of CD158j and perform on CD4+ CD28null cells was analyzed with flow cytometry in 106 CI patients with carotid atherosclerosis, 33 CI patients with normal carotid arteries and in 50 normal controls, respectively; p-ERK expression was assayed with flow cytometry in 36 CI patients with unstable plaque, and serum IFN-γ was detected with ELISA. The intima-media thickness (IMT) of bilateral carotid arteries in all subjects was confirmed by the colour Doppler ultrasonograph imagingResults Percentage of the CD4+ CD28null T cells, expression of CD158j and perform on CD4+ CD28null T cells and the serum IFN-γ levels was dramatically higher in CI patients than that in normal controls, respectively (all P <0.01), which was decreased in an order of CI patients with patients with unstable plaque, stable plaque, carotid artery IMT and with normal carotid artery. A strong positive correlation was observed between the CD158j expression and degree of p-ERK in CI patients with unstable plaque (P < 0. 01). Conclusion CD4+ CD28null T cells were significantly increased in CI patients with carotid atherosclerosis. CD158j might up-regulate p-ERK expression and induce the proliferation of the CD4+ CD28nullT cells; consequently, higher cytokine production such as IFN-γ produced by CD4+ CD28null T cells may cause the formation of unstable plaque.     

伴颈动脉粥样硬化脑梗患者CD4+CD28null T细胞CD158j表达和ERK磷酸化水平的关系

目的 探讨伴颈动脉粥样硬化(CA)脑梗患者CD4+CD28null T细胞上CD158j的表达百分率和ERK磷酸化(p-ERK)水平的关系及对颈动脉粥样斑块不稳定的影响.方法 采用流式细胞术检测106例伴CA脑梗、33例颈动脉正常脑梗患者和50例健康人外周血CD4+CD28null T细胞数量,以及CD4+CD28null T细胞CD158j和穿孔素(perforin)的表达,36例斑块不稳定患者CD4+T细胞p-ERK水平.ELISA法检测血清IFN-γ水平.B超检查以上人群颈动脉血管内壁粥样硬化情况.结果 脑梗患者CD4+CD28nullT细胞数量、CD4+CD28null T细胞CD158j和perforin的表达,以及血清IFN-γ水平,均明显高于健康对照组(P均<0.01);CD4+CD28null T细胞数量、CD4+CD28null T细胞CD158j和perforin的表达,以及血清IFN-γ水平,在脑梗患者中由高到低依次为颈动脉不稳定斑块组、颈动脉稳定斑块组、颈动脉内-中膜厚度(IMT)增厚组和颈动脉正常组.颈动脉不稳定斑块脑梗患者CD4+CD28null T细胞CD158j的表达与p-ERK水平呈显著性正相关(P<0.01).结论 伴CA脑梗患者CD4+CD28null T细胞数量明显增多.CD158j可能通过上调p-ERK水平,促进CD4+CD28null淋巴细胞增殖,产生细胞毒效应和分泌细胞因子,最终导致颈动脉粥样斑块不稳定.

Abstract：

Objective To investigate the relationship between CD158j expression and phosphorylated ERK (p-ERK) in CD4+ CD28null T cells in cerebral infarction (CI) patients- with carotid atherosclerosis and its effects on carotid atherosclerotic plaque stability. Methods Percentage of peripheral CD4+ CD28null and the expression of CD158j and perform on CD4+ CD28null cells was analyzed with flow cytometry in 106 CI patients with carotid atherosclerosis, 33 CI patients with normal carotid arteries and in 50 normal controls, respectively; p-ERK expression was assayed with flow cytometry in 36 CI patients with unstable plaque, and serum IFN-γ was detected with ELISA. The intima-media thickness (IMT) of bilateral carotid arteries in all subjects was confirmed by the colour Doppler ultrasonograph imagingResults Percentage of the CD4+ CD28null T cells, expression of CD158j and perform on CD4+ CD28null T cells and the serum IFN-γ levels was dramatically higher in CI patients than that in normal controls, respectively (all P <0.01), which was decreased in an order of CI patients with patients with unstable plaque, stable plaque, carotid artery IMT and with normal carotid artery. A strong positive correlation was observed between the CD158j expression and degree of p-ERK in CI patients with unstable plaque (P < 0. 01). Conclusion CD4+ CD28null T cells were significantly increased in CI patients with carotid atherosclerosis. CD158j might up-regulate p-ERK expression and induce the proliferation of the CD4+ CD28nullT cells; consequently, higher cytokine production such as IFN-γ produced by CD4+ CD28null T cells may cause the formation of unstable plaque.     

Instruction of naive CD4+ T cells by polarized CD4+ T cells within dendritic cell clusters

Cooperation between CD4(+) T cells can enhance the response and modulate the cytokine profile, and defining these parameters has become a major issue for multivalent-vaccine strategies.We explored cooperation using adoptive transfer of two populations of TCR transgenic T cells of different specificity. One was transferred without prior activation, whereas the second was activated for five days by antigen stimulation under polarizing culture conditions. Both populations were transferred into a single adoptive host and then primed by particle-mediated DNA delivery. Polarized Th1 cells (inducers) raised the frequency of IFN-gamma(+) cells within a naive (target) population, whereas Th2 inducers raised the frequency of IL-4(+) and reduced that of IL-2(+) cells. These effects were obtained when the genes for both antigens were on the same particle, favoring presentation by the same dendritic cell, but not when on different particles delivered to different dendritic cells. Autonomy of DC clusters allows linked sets of antigens (e.g. from a single pathogen) to maintain cytokine bias, but allows other independent responses, each with their own set of autonomous clusters.     

RA患者外周血CD8＋CD28-和CD4＋CD25＋调节性T细胞的表达及疾病活动性指标相关性分析

目的：检测类风湿性关节炎（RA）患者外周血CD8＋CD28-、CD4＋CD25＋调节性T细胞亚群,探讨其与临床活动性指标的关系。方法：采用流式细胞术检测台州医院RA患者外周血CD8＋CD28-、CD4＋CD25＋ T细胞亚群比例,探讨调节性T细胞与RA活动性、类风湿因子（RF）、免疫球蛋白（Ig）、C反应蛋白（CRP）、补体C3、抗CCP抗体、抗核抗体（ANA）、血小板（PLT）及血沉（ESR）的关系。结果：活动期RA患者外周血CD4＋CD25＋调节性T细胞亚群比例显著低于正常对照组（P〈0.01）,但稳定期RA患者与正常对照组结果差异无统计学意义（P〉0.05）。活动期和稳定期RA患者CD8＋CD28-与正常对照组相比较,结果无统计学意义（P〉0.05）;CD4＋CD25＋与CRP密切相关（r=-0.593,P〈0.05）,CD8＋CD28-与ESR相关系数呈弱相关。CD4＋CD25＋和CD8＋CD28-细胞与RF、IGG、C3、ANA、anti-CCP和PLT未见明显相关性。结论：活动期RA患者外周血CD4＋CD25＋ T细胞亚群比例减少,CD4＋CD25＋ T细胞可能与类风湿性关节炎疾病进展有关。     

CD30 expression on circulating memory CD4+ T cells as a Th2-dominated situation in patients with atopic dermatitis

Th2 clones have been reported to express CD30 preferentially, but whether T cells producing Th2-type cytokines may favor CD30 expression in the in vivo state remains unknown. We investigated the expression of CD30 on circulating T cells in atopic dermatitis (AD) as a Th2-dominated disorder. Peripheral blood mononuclear cells were prepared from 51 AD patients and 14 nonatopic controls, and their phenotypes were analyzed with flow cytometry. Cytokine production by stimulated CD4+ T cells was also assessed by the single-cell-staining method. Flow cytometric analysis clearly revealed that CD30+ T cells were identifiable in the blood of AD patients with greater frequency compared to controls. The important finding was that CD30 expression was restricted to a small but substantial population of memory (CD45RO+) CD4+ T cells, but not CD8+ ones. In AD patients, it was demonstrated that the percentages of CD30+ cells within CD45RO+ CD4+ T cells correlated well with the disease severity, serum IgE levels, peripheral eosinophil counts, and tendency toward Th2-dominant cytokine pattern as determined by the ratio of interleukin-4 to interferon-gamma production. This study suggests that CD30 expression in circulating T cells might serve as an in vivo marker for the Th2-dominated condition.     

CD8+ CD28- and CD8+ CD57+ T cells and their role in health and disease

Chronic antigenic stimulation leads to gradual accumulation of late-differentiated, antigen-specific, oligoclonal T cells, particularly within the CD8(+) T-cell compartment. They are characterized by critically shortened telomeres, loss of CD28 and/or gain of CD57 expression and are defined as either CD8(+) CD28(-) or CD8(+) CD57(+) T lymphocytes. There is growing evidence that the CD8(+) CD28(-) (CD8(+) CD57(+)) T-cell population plays a significant role in various diseases or conditions, associated with chronic immune activation such as cancer, chronic intracellular infections, chronic alcoholism, some chronic pulmonary diseases, autoimmune diseases, allogeneic transplantation, as well as has a great influence on age-related changes in the immune system status. CD8(+) CD28(-) (CD8(+) CD57(+)) T-cell population is heterogeneous and composed of various functionally competing (cytotoxic and immunosuppressive) subsets thus the overall effect of CD8(+) CD28(-) (CD8(+) CD57(+)) T-cell-mediated immunity depends on the predominance of a particular subset. Many articles claim that CD8(+) CD28(-) (CD8(+) CD57(+)) T cells have lost their proliferative capacity during process of replicative senescence triggered by repeated antigenic stimulation. However recent data indicate that CD8(+) CD28(-) (CD8(+) CD57(+)) T cells can transiently up-regulate telomerase activity and proliferate under certain stimulation conditions. Similarly, conflicting data is provided regarding CD8(+) CD28(-) (CD8(+) CD57(+)) T-cell sensitivity to apoptosis, finally leading to the conclusion that this T-cell population is also heterogeneous in terms of its apoptotic potential. This review provides a comprehensive approach to the CD8(+) CD28(-) (CD8(+) CD57(+)) T-cell population: we describe in detail its origins, molecular and functional characteristics, subsets, role in various diseases or conditions, associated with persistent antigenic stimulation.     

CD4-mediated functional activation of human CD4+CD25+ regulatory T cells

Naturally occurring CD4(+)CD25(+)FoxP3(+) regulatory T cells (CD25(+) Tregs) constitute a specialized population of T cells that is essential for the maintenance of peripheral self-tolerance. The immune regulatory function of CD25(+) Tregs depends upon their activation. We found that anti-CD4 antibodies activate the suppressive function of human CD25(+) Tregs in a dose-dependent manner. We demonstrate that CD4-activated CD25(+) Tregs suppress the proliferation of CD4(+) and CD8(+) T cells, their IL-2 and IFN-gamma production as well as the capacity of CD8(+) T cells to re-express CD25. By contrast, anti-CD4 stimulation did not induce suppressive activity in conventional CD4(+) T cells. These results identify CD4 as a trigger for the suppressive function of CD25(+) Tregs and suggest a possible CD4-mediated exploitation of these cells.     

CD28-deficient mice generate an impaired Th2 response to Schistosoma mansoni infection

Engagement of CD28 on T cells provides a co-stimulatory signal necessary for T cell activation and differentiation. Recent findings suggest that priming of T helper (Th)2 cells is more dependent on CD28 activation than Th1 cells. The present study examines whether mice that lack expression of CD28 as a result of gene targeting are capable of generating a Th2 response characteristic during infection with the intravascular trematode parasite Schistosoma mansoni. Mutant and control mice were either inoculated in the footpad with S. mansoni eggs (a potent inducer of a Th2 response) or infected percutaneously with the parasite. Draining lymph nodes (after footpad injection) or spleen cells (after natural infection) were harvested at 12 days and 8 weeks, respectively, and examined for cytokine responses to egg antigens. CD28-deficient mice (−/−) generated diminished egg antigen-driven interleukin (IL)-4 and IL-5 production (by 5- to 17-fold, respectively) compared to CD28-expressing (+/+) littermates. In contrast, lymphocyte proliferation and interferon (IFN)-γ production to egg antigens were equivalent for mutant and control mice. Infected CD28−/− mice also had reduced immunoglobulin secretion. Serum levels of parasite antigen-specific IgG1 and polyclonal IgE were significantly diminished in CD28−/− compared to CD28+/+ mice. Lack of CD28 expression had no effect on granuloma formation around eggs trapped in the liver, but increased susceptibility of mice to primary schistosomiasis infection. These studies indicate that CD28 activation contributes to T cell priming required for generation of a Th2 response to an intravascular dwelling helminth parasite.