99Tcm-甲氧基异丁基异腈双时相平面显像和SPECT/CT断层显像诊断原发性甲状旁腺功能亢进症

目的 观察⁹⁹Tc^m-甲氧基异丁基异腈（⁹⁹Tc^m-MIBI）双时相平面显像和SPECT/CT断层显像诊断原发性甲状旁腺功能亢进症（PHPT）的价值。方法 收集术前接受⁹⁹Tc^m-MIBI双时相平面显像和SPECT/CT断层显像的疑似PHPT患者40例,所有患者均接受手术治疗。以术后病理诊断为金标准,计算并比较⁹⁹Tc^m-MIBI双时相平面显像和SPECT/CT断层显像诊断PHPT的灵敏度。结果 40例中,38例经病理确诊为PHPT,⁹⁹Tc^m-MIBI双时相平面显像灵敏度为89.47%（34/38）,⁹⁹Tc^m-MIBI SPECT/CT断层显像灵敏度为94.74%（36/38）,差异无统计学意义（P>0.05）。对不同病灶大小及不同甲状旁腺素水平PHPT,⁹⁹Tc^m-MIBI双时相平面显像与SPECT/CT断层显像诊断灵敏度差异均无统计学意义（P均>0.05）。结论 ⁹⁹Tc^m-MIBI双时相平面显像和SPECT/CT断层显像诊断PHPT灵敏度高。     

多模态影像学术前定位诊断原发性及继发于慢性肾病的甲状旁腺功能亢进症

目的 对比⁹⁹Tc^m-MIBI双时相平面显像、SPECT/CT显像与超声术前定位诊断原发性甲状旁腺功能亢进症(PHPT)及继发于慢性肾病的甲状旁腺功能亢进症(SHPT)的价值。方法 纳入113例术前接受⁹⁹Tc^m-MIBI双时相平面显像、SPECT/CT显像和颈部超声检查的甲状旁腺功能亢进症(HPT)患者,包括95例PHPT及18例慢性肾病SHPT;以术后病理为标准,分析各影像学方法术前定位诊断的价值。结果 术后病理共于95例PHPT中诊断108处病灶,其中90处显像阳性、18处阴性;于18例慢性肾病后SHPT中诊断46处病灶,其中44处显像阳性、2处阴性。双时相平面显像、SPECT/CT显像和超声定位诊断PHPT的准确率分别为87.96%(95/108)、92.59%(100/108)和79.63%(86/108),定位诊断慢性肾病后SHPT准确率分别为58.70%(27/46)、86.96%(40/46)和71.74%(33/46),双时相平面显像对前者显著高于后者(P＜0.001)。双时相平面显像、SPECT/CT显像及超声诊断PHPT准确率差异均无统计学意义(P均＞0.05);对于慢性肾病后SHPT,SPECT/CT显像诊断准确性率显著高于双时相平面显像(P=0.004)而与超声差异无统计学意义(P=0.121),双时相平面显像与超声差异亦无统计学意义(P=0.274)。结论 ⁹⁹Tc^m-MIBI双时相平面显像、SPECT/CT显像及超声术前定位诊断HPT准确率较高。双时相平面显像诊断PHPT效能优于慢性肾病后SPHT;推荐对慢性肾病后SHPT优先行SPECT/CT显像。     

不同影像学检查方法对原发性甲状旁腺功能亢进症患者甲状旁腺病灶的定位诊断价值

目的 探讨不同影像学检查方法对原发性甲状旁腺功能亢进症（PHPT）的诊断价值。方法 回顾性分析经病理学检查证实的109例PHPT患者的临床资料,将其超声、MRI、CT、⁹⁹Tc^m-MIBI检查定位诊断结果与手术后病理学结果比较分析。结果 109例PHPT中,甲状旁腺癌11例（11/109,10.09%）,增生16例（16/109,14.67%）,甲状旁腺瘤82例（82/109,75.23%）,包括单发病灶74例（74/109,67.89%）,双侧腺瘤8例（8/109,7.34%）。腺瘤、增生、腺癌组病灶发生部位的差异有统计学意义（χ²=36.151,P<0.001）。⁹⁹Tc^m-MIBI、MRI、CT、超声术前检查定位的准确率分别为83.50%（81/97）、72.22%（13/18）、68.51%（37/54）、67.67%（67/99）,差异无统计学意义（χ²=4.826,P=0.185）;超声明显低于⁹⁹Tc^m-MIBI检查（χ²=6.638, P=0.001）,CT明显低于⁹⁹Tc^m-MIBI检查（χ²=4.562,P=0.033）,CT与MRI的定位诊断准确率差异无统计学意义（χ²=1.153,P=0.283）。对于术后病理诊断直径<1 cm的病变,⁹⁹Tc^m-MIBI、超声、CT、MRI术前检查定位的准确率分别为77.27%（17/22）、35.00%（7/20）、61.53%（8/13）、66.67%（2/3）,差异有统计学意义（χ²=7.881,P=0.049）,⁹⁹Tc^m-MIBI的定位准确率高于超声（χ²=7.664,P=0.006）,但与CT、MRI的差异无统计学意义（χ²=2.154,P=0.175）。结论 对PHPT进行定位诊断时,超声仍是首选检查,⁹⁹Tc^m-MIBI双时相显像的诊断价值最高。     

比较18F-氟代胆碱PET/CT、99Tcm-甲氧基异丁基异腈SPECT/CT及超声诊断甲状旁腺功能亢进症

目的 比较¹⁸F-氟代胆碱（FCH） PET/CT、⁹⁹Tc^m-甲氧基异丁基异腈（MIBI） SPECT/CT及超声（US）诊断甲状旁腺功能亢进症（HPT）的效能。方法 回顾性分析34例HPT患者,术前2个月内均接受¹⁸F-FCH PET/CT、⁹⁹Tc^m-MIBI SPECT/CT及US检查;以术中及术后病理结果为参考,评估并比较各方法的诊断效能。结果 于34例共切除90处甲状旁腺病灶,病理证实其中81处为甲状旁腺增生或腺瘤组织,7处为甲状腺组织,2处为淋巴结。¹⁸F-FCH PET/CT诊断HPT的敏感度、特异度、阳性预测值、阴性预测值及准确率分别为85.19%（69/81）、100%（55/55）、100%（69/69）、82.09%（55/67）及91.18%（124/136）,⁹⁹Tc^m-MIBI SPECT/CT分别为74.07%（60/81）、90.91%（50/55）、92.31%（60/65）、70.42%（50/71）及80.88%（110/136）,US分别为65.43%（53/81）、98.18%（54/55）、98.15%（53/54）、65.85%（54/82）及78.68%（107/136）。¹⁸F-FCH PET/CT诊断HPT的效能高于⁹⁹Tc^m-MIBI SPECT/CT和US （Z=2.290,P=0.022;Z=2.496,P=0.013）。结论 ¹⁸F-FCH PET/CT、⁹⁹Tc^m-MIBI SPECT/CT及US 3种方法中,¹⁸F-FCH PET/CT诊断HPT的效能最高。     

99Tcm-MIBI SPECT/CT诊断甲状腺乳头状癌术后彩色多普勒超声疑似颈部淋巴结转移

目的 评估⁹⁹Tc^m-MIBI SPECT/CT诊断甲状腺乳头状癌（PTC）术后彩色多普勒超声（CDUS）疑似颈部淋巴结转移的价值。方法 收集31例PTC术后CDUS疑似颈部淋巴结转移患者，均于术后1个月内接受颈部⁹⁹Tc^m-MIBI SPECT/CT扫描，之后15天内接受颈部¹³¹I SPECT/CT扫描。观察⁹⁹Tc^m-MIBI SPECT/CT对于PTC术后颈部淋巴结转移的诊断效率。结果 31例中，6例（6/31，19.35%）存在颈部淋巴结转移。⁹⁹Tc^m-MIBI SPECT/CT对PTC术后颈部淋巴结转移的敏感度、特异度、准确率、阳性预测值和阴性预测值分别为66.67%（4/6）、96.00%（24/25）、90.32%（28/31）、80.00%（4/5）和92.31%（24/26）。共确定14个颈部淋巴结转移灶，⁹⁹Tc^m-MIBI SPECT/CT诊断敏感度和阳性预测值分别为71.43%（10/14）和83.33%（10/12），首次¹³¹I SPECT/CT为28.57%（4/14）和100%（4/4），⁹⁹Tc^m-MIBI SPECT/CT的敏感度高于¹³¹I SPECT/CT（χ²=5.14，P<0.05），其阳性预测值与首次¹³¹I SPECT/CT差异无统计学意义（Fisher精确概率法，P>0.05）。结论 ⁹⁹Tc^m-MIBI SPECT/CT能确定大部分PTC颈部淋巴结转移灶，为判断¹³¹I SPECT/CT和CDUS疑似淋巴结转移提供更多信息。     

99Tcm-MIBI SPECT/CT联合D-二聚体鉴别诊断口腔颌面部病变良恶性

目的 探讨⁹⁹Tc^m-MIBI SPECT/CT显像联合血浆D-二聚体检测鉴别诊断口腔颌面部病变良恶性的价值。方法 对57例经病理确诊的口腔颌面部肿块患者行⁹⁹Tc^m-MIBI SPECT/CT显像并测量血浆D-二聚体,以术后病理结果为金标准,计算并比较⁹⁹Tc^m-MIBI SPECT/CT显像与血浆D-二聚体两种方法单独及联合诊断口腔额面部恶性肿瘤的灵敏度（敏感度）、特异度及准确率。结果 ⁹⁹Tc^m-MIBI SPECT/CT显像和血浆D-二聚体检测单独及联合诊断口腔颌面部恶性肿瘤的灵敏度（敏感度）、特异度、准确率分别为72.73%（16/22）、82.86%（29/35）、78.95%（45/57）,68.18%（15/22）、74.29%（26/35）、71.93%（41/57）及95.45%（21/22）、94.29%（33/35）、94.74%（54/57）,联合诊断恶性肿瘤的敏感度和准确率高于⁹⁹Tc^m-MIBI SPECT/CT（P均<0.05）,联合诊断敏感度、特异度和准确率均高于D-二聚体检测（P均<0.05）。结论 ⁹⁹Tc^m-MIBI SPECT/CT显像与血浆D-二聚体检测联合应用可提高二者单独应用鉴别口腔颌面部病变良恶性的效能,具有重要临床价值。     

99Tcm-MDP SPECT/CT显像诊断乳腺癌骨转移

目的 评价⁹⁹Tc^m-MDP SPECT/CT显像对全身骨显像难以确诊的乳腺癌骨转移的诊断价值。方法 回顾分析⁹⁹Tc^m-MDP全身骨显像难以确诊的132例乳腺癌患者共210个骨转移灶的影像资料。以临床随访及病理检查获得最终诊断结果,计算⁹⁹Tc^m-MDP SPECT/CT显像对骨转移灶的诊断准确率、灵敏度、特异度、阳性预测值及阴性预测值。并对比不同部位病灶的诊断准确率差异。结果 210个病灶中, ⁹⁹Tc^m-MDP SPECT/CT正确诊断骨转移灶82个,良性病灶112个,诊断准确率为92.38%(194/210),灵敏度为94.25%(82/87),特异度为91.05%(112/123),阳性预测值为88.17%(82/93),阴性预测值为95.72%(112/117)。⁹⁹Tc^m-MDP SPECT/CT对脊椎病灶的诊断准确率明显高于肋骨病灶(χ²=7.81,P<0.05)。结论 利用⁹⁹Tc^m-MDP SPECT/CT显像对全身骨显像难以诊断的乳腺癌骨转移灶进行诊断,具有较高的诊断效能。     

低剂量SPECT/CT对甲状腺良恶性结节鉴别的增益价值

目的 评价低剂量SPECT/CT在鉴别甲状腺良恶性结节中的增益价值。方法 收集触诊/彩色多普勒超声考虑甲状腺结节患者41例，分别行⁹⁹Tc^mO_4-平面显像和低剂量SPECT/CT融合显像，以病理结果为金标准，比较2者诊断效能。结果 低剂量SPECT/CT融合显像诊断甲状腺结节良恶性的灵敏度、特异度、准确率及受试者工作特征（ROC）曲线下面积（AUC）分别为61.90%、53.33%、63.41%和0.64；均高于^99mTcO_4-平面显像的19.05%、45.00%、31.70%和0.32（P均<0.05）。结论 低剂量SPECT/CT对恶性甲状腺结节的诊断效能优于⁹⁹Tc^mO_4-平面显像。     

99Tcm-MDP SPECT/CT诊断宫颈癌放疗后骨盆不全骨折

目的 探讨⁹⁹Tc^m-MDP SPECT/CT诊断宫颈癌放疗后骨盆不全骨折（PIF）的价值。方法 回顾性分析37例宫颈癌放疗后疑似PIF患者的全身显像（WBS）和骨盆SPECT/CT断层融合显像资料。以影像学资料、临床资料及随访（>12个月）结果作为最终诊断PIF的标准,比较WBS、SPECT/CT对PIF的诊断效能。结果 37例患者共50个骨盆病灶,最终诊断PIF 42个（30例）。WBS诊断PIF的灵敏度为45.24%（19/42）,特异度50.00%（4/8）,准确率46.00%（23/50）;SPECT/CT诊断PIF的灵敏度为92.86%（39/42）,特异度75.00%（6/8）,准确率90.00%（45/50）;SPECT/CT诊断宫颈癌放疗后PIF的灵敏度及准确率均高于WBS（χ²=22.28、22.24,P均<0.01）,但二者特异度差异无统计学意义（P=0.31）。结论 ⁹⁹Tc^m-MDP SPECT/CT可用于诊断宫颈癌放疗后PIF。     

剪切波弹性成像与99Tcm-MIBI SPECT显像对比诊断甲状腺癌

目的 比较剪切波弹性成像与⁹⁹Tc^m-MIBI SPECT显像诊断甲状腺癌的价值。方法 以118个甲状腺结节作为研究对象,行剪切波弹性成像及⁹⁹Tc^m-MIBI SPECT显像。以病理为金标准,计算并比较两种方法对甲状腺癌结节的诊断敏感度（灵敏度）、特异度、准确度、阳性预测值及阴性预测值,并进行率的比较。结果 剪切波弹性成像与⁹⁹Tc^m-MIBI SPECT显像诊断甲状腺癌的敏感度（灵敏度）、特异度、准确率、阳性预测值及阴性预测值分别为88.57%（31/35）和62.86%（22/35）、89.16%（74/83）和65.06%（54/83）、88.98%（105/118）和64.41%（76/118）、77.50%（31/40）和43.14%（22/51）、94.87%（74/78）和80.60%（54/67）,差异均有统计学意义（P<0.05）。结论 剪切波弹性成像对甲状腺癌的诊断效能优于⁹⁹Tc^m-MIBI SPECT显像。     

Temporal and spatial characterization of negative regulatory T cells in HIV‐infected/AIDS patients raises new diagnostic markers and therapeutic strategies

BackgroundNegative regulatory T cells (Tregs) not only deplete effector T cells but also inhibit the clearance of HIV during infection, which may allow Tregs to be used as informative diagnostic markers. To facilitate both diagnosis and treatment, a thorough understanding of these regulators by characterizing them on temporal and spatial scales is strongly required.MethodsHundred HIV‐infected/AIDS patients, including 87 males, with an average age of 35.8 years, as well as 20 healthy controls, were enrolled. Flow cytometry was used to analyze CD3+T cells, CD4+T cells, and CD8+T cells to evaluate the immune status of the participants. Then, a group of representative negative regulatory T cells, including CD4+PD‐1+T cells, CD4+PD‐1^highT cells, CD8+PD‐1+T cells, and CD4+CD25^high Tregs was also analyzed to explore their effects on disease progression and intercorrelation.ResultsThe percentages of CD4⁺PD‐1⁺T cells and CD4⁺CD25^highTregs increased in patients with the same ultrahigh significance. Temporally, the patients with both intermediate‐stage and late‐stage disease had higher percentages of CD4⁺PD‐1⁺T cells; however, the percentage of CD4⁺CD25^highTregs only increased in the patients with late‐stage disease. In addition, CD4⁺PD‐1⁺T cells but not CD4⁺CD25^highTregs were negatively correlated with the absolute CD4⁺T cell count. Spatially, no correlations between CD4⁺PD‐1⁺T cells and CD4⁺CD25^highTregs were observed, which suggests these Tregs function differently during immunosuppression.ConclusionsThis study characterized negative regulatory T cells in HIV‐infected/AIDS patients at both temporal and spatial scales and found that CD4⁺CD25⁺Tregs and CD4⁺PD‐1⁺T cells could be used as potential diagnostic markers for identifying different disease stages and monitoring disease progression.     

99Tcm-3PEG4-RGD用于家兔易损斑块分子显像

目的 探讨通过探测兔新生微血管活体评价动脉易损斑块的可行性。方法 将15只雄性新西兰大白兔随机分成普食对照组（A组）、易损斑块组（B组）和稳定斑块组（C组）,每组5只。于喂养2周后分别进行股动脉分离假手术（A、C组）和腹主动脉球囊拉伤术（B组）,之后喂养不同成分饲料。于4、8、12周末静脉注射⁹⁹Tc^m-3PEG4-RGD,注射后0.5 h、1 h、2 h行SPECT/CT显像及同机CT平扫。4、8周末显像后对3组各处死1只实验兔,12周末处死剩余动物,行离体血管SPECT显像、病理及免疫组化染色分析。结果 3组实验兔注射⁹⁹Tc^m-3PEG4-RGD后0.5 h SPECT/CT图像显示,4周后3组兔腹主动脉区均未见放射性摄取增高,T/NT值差异无统计学意义（F=2.515,P=0.122）;8周后B、C组局部放射性摄取增高（F=17.037,P=0.001）;12周后B组腹主动脉局部放射性摄取明显高于A、C组（F=43.710,P<0.001）。8、12周末,B、C组腹主动脉中均含有新生微血管,且B组数量明显高于C组。B组兔腹主动脉斑块的AHA动脉粥样硬化分型为Ⅲ型及Ⅳ型,C组为AHA Ⅱ型。A组腹主动脉中无新生微血管及易损斑块。结论 ⁹⁹Tc^m-3PEG4-RGD分子显像对无创性评价兔动脉斑块稳定性具有一定价值。     

In vivo cytotoxic T lymphocyte elicitation by mycobacterial heat shock protein 70 fusion proteins maps to a discrete domain and is CD4(+) T cell independent

To gain insights into the mechanisms by which soluble heat shock protein (hsp) fusions can elicit CD8(+) cytotoxic T lymphocytes (CTLs) against the fusion partner, mycobacterial (Mycobacterium tuberculosis) hsp70 was dissected to ascertain whether a particular hsp domain is necessary, and knockout mice were used to determine whether the fusion protein's immunogenicity is dependent on CD4(+) T lymphocytes. We found that the ability to elicit CD8(+) CTLs depends on a discrete 200-amino acid protein domain, indicating that the fusion protein's immunogenicity for CD8(+) T cells does not require coupled chaperone function or peptide binding. Further, we found that ovalbumin (OVA).hsp70 fusion protein elicited anti-OVA CD8(+) CTLs about equally well in CD4 knockout and wild-type C57BL/6 mice, and also when the hsp70 was of murine (self) origin. The ability of hsp70 fusion proteins to elicit CD4-independent CTL responses suggests that hsp70 fusion proteins may be useful for immunological prophylaxis and therapy against disease in CD4(+) T cell-deficient individuals.     

High level expression of CD43 inhibits T cell receptor/CD3-mediated apoptosis

In a screen designed to identify genes that regulate T cell receptor (TCR)/CD3-mediated apoptosis, we found that high level expression of CD43 protected T cell hybridomas from activation-induced cell death. The protection appears to result from its capacity to block Fas-mediated death signals rather than from inhibition of the upregulation of Fas and/or Fas ligand after T cell stimulation. We found that peripheral CD4(+) T cells can be divided into two subsets based on the level of CD43 surface expression. The CD4(+)CD43(low) subset exhibits a naive T cell phenotype, being CD62L(high)CD45RB(high)CD44(low), whereas CD4(+)CD43(high) cells exhibit a memory phenotype, being CD62L(low)CD45RB(low)CD44(high). Recent studies have demonstrated that engagement of TCR and Fas induces naive CD4(+) T cells to undergo apoptosis, and the same treatment enhances the proliferation of memory CD4(+) T cells. We confirm here that peripheral CD4(+)CD43(high) T cells are resistant to TCR/CD3-mediated cell death. These results suggest that the expression levels of CD43 on naive and memory CD4(+) T cells determine their susceptibility to Fas-dependent cell death and that high level expression of CD43 may be used as a marker to define CD4(+) memory T cells. Expression of CD43 provides a novel mechanism by which tumor cells expressing abnormally high levels of CD43 may escape Fas-mediated killing.     

In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes

The low number of CD4+ CD25+ regulatory T cells (Tregs), their anergic phenotype, and diverse antigen specificity present major challenges to harnessing this potent tolerogenic population to treat autoimmunity and transplant rejection. In this study, we describe a robust method to expand antigen-specific Tregs from autoimmune-prone nonobese diabetic mice. Purified CD4+ CD25+ Tregs were expanded up to 200-fold in less than 2 wk in vitro using a combination of anti-CD3, anti-CD28, and interleukin 2. The expanded Tregs express a classical cell surface phenotype and function both in vitro and in vivo to suppress effector T cell functions. Most significantly, small numbers of antigen-specific Tregs can reverse diabetes after disease onset, suggesting a novel approach to cellular immunotherapy for autoimmunity.     

gp100/pmel 17 Is a Murine Tumor Rejection Antigen: Induction of “Self”-reactive,Tumoricidal T Cells Using High-affinity,Altered Peptide Ligand

Many tumor-associated antigens are nonmutated, poorly immunogenic tissue differentiation antigens. Their weak immunogenicity may be due to “self”-tolerance. To induce autoreactive T cells, we studied immune responses to gp100/pmel 17, an antigen naturally expressed by both normal melanocytes and melanoma cells. Although a recombinant vaccinia virus (rVV) encoding the mouse homologue of gp100 was nonimmunogenic, immunization of normal C57BL/6 mice with the rVV encoding the human gp100 elicited a specific CD8⁺ T cell response. These lymphocytes were cross-reactive with mgp100 in vitro and treated established B16 melanoma upon adoptive transfer. To understand the mechanism of the greater immunogenicity of the human version of gp100, we characterized a 9-amino acid (AA) epitope, restricted by H-2D^b, that was recognized by the T cells. The ability to induce specific T cells with human but not mouse gp100 resulted from differences within the major histocompatibility complex (MHC) class I–restricted epitope and not from differences elsewhere in the molecule, as was evidenced by experiments in which mice were immunized with rVV containing minigenes encoding these epitopes. Although the human (hgp100_25–33) and mouse (mgp100_25–33) epitopes were homologous, differences in the three NH₂-terminal AAs resulted in a 2-log increase in the ability of the human peptide to stabilize “empty” D^b on RMA-S cells and a 3-log increase in its ability to trigger interferon γ release by T cells. Thus, the fortuitous existence of a peptide homologue with significantly greater avidity for MHC class I resulted in the generation of self-reactive T cells. High-affinity, altered peptide ligands might be useful in the rational design of recombinant and synthetic vaccines that target tissue differentiation antigens expressed by tumors.     

Role for CD4(+) CD25(+) regulatory T cells in reactivation of persistent leishmaniasis and control of concomitant immunity

Reactivation of dormant infections causes an immense burden of morbidity and mortality in the world at large. Reactivation can occur as a result of immunosuppression, environmental insult, or aging; however, the cause of reactivation of such infections is often not clear. We have previously shown that persistence of the parasite Leishmania major is controlled by endogenous CD4(+) CD25(+) regulatory T (T reg) cells. In this report, we show that despite efficient parasite clearance at secondary sites of infection, Leishmania superinfection can cause disease reactivation at the primary site. Our results strongly suggest that T reg cells, whose numbers increase in sites of reactivation, are directly responsible for such reactivation. Depletion of CD25(+) cells at the time of secondary challenge prevented disease reactivation at the site of persistent infection while strengthening the expression of immunity at the site of secondary challenge. Finally, transfer of T reg cells purified from infected mice into chronically infected mice was sufficient to trigger disease reactivation and prevent the expression of an effector memory response. Our results demonstrate that after persistence is achieved, an equilibrium between T reg cells and effector lymphocytes, which can be disturbed by superinfection, controls the efficiency of recall immune responses and disease reactivation.     

CD40-independent pathways of T cell help for priming of CD8(+) cytotoxic T lymphocytes

In many cases, induction of CD8(+) CTL responses requires CD4(+) T cell help. Recently, it has been shown that a dominant pathway of CD4(+) help is via antigen-presenting cell (APC) activation through engagement of CD40 by CD40 ligand on CD4(+) T cells. To further study this three cell interaction, we established an in vitro system using dendritic cells (DCs) as APCs and influenza hemagglutinin (HA) class I and II peptide-specific T cell antigen receptor transgenic T cells as cytotoxic T lymphocyte precursors and CD4(+) T helper cells, respectively. We found that CD4(+) T cells can provide potent help for DCs to activate CD8(+) T cells when antigen is provided in the form of either cell lysate, recombinant protein, or synthetic peptides. Surprisingly, this help is completely independent of CD40. Moreover, CD40-independent CD4(+) help can be documented in vivo. Finally, we show that CD40-independent T cell help is delivered through both sensitization of DCs and direct CD4(+)-CD8(+) T cell communication via lymphokines. Therefore, we conclude that CD4(+) help comprises at least three components: CD40-dependent DC sensitization, CD40-independent DC sensitization, and direct lymphokine-dependent CD4(+)-CD8(+) T cell communication.     

Loss of HIV-1-specific CD8+ T cell proliferation after acute HIV-1 infection and restoration by vaccine-induced HIV-1-specific CD4+ T cells

Virus-specific CD8(+) T cells are associated with declining viremia in acute human immunodeficiency virus (HIV)1 infection, but do not correlate with control of viremia in chronic infection, suggesting a progressive functional defect not measured by interferon gamma assays presently used. Here, we demonstrate that HIV-1-specific CD8(+) T cells proliferate rapidly upon encounter with cognate antigen in acute infection, but lose this capacity with ongoing viral replication. This functional defect can be induced in vitro by depletion of CD4(+) T cells or addition of interleukin 2-neutralizing antibodies, and can be corrected in chronic infection in vitro by addition of autologous CD4(+) T cells isolated during acute infection and in vivo by vaccine-mediated induction of HIV-1-specific CD4(+) T helper cell responses. These data demonstrate a loss of HIV-1-specific CD8(+) T cell function that not only correlates with progressive infection, but also can be restored in chronic infection by augmentation of HIV-1-specific T helper cell function. This identification of a reversible defect in cell-mediated immunity in chronic HIV-1 infection has important implications for immunotherapeutic interventions.