FoxP3+ CD4+ CD25+调节性T细胞在重症肌无力发病机制中的作用

目的 在细胞与分子水平检验重症肌无力(myasthenia gravis,MG)患者外周血中CD4+CD25+调节性T细胞(CD4+CD25+Tregs)的表达缺陷,探讨CD4+CD25+Tregs亚群异常与MG发病间的关系.方法 流式细胞技术检测21例MG患者(11例经胸腺切除)与20名健康对照者(healthy controls,HCs)外周血CD4+CD25+Tregs及FoxP3+CD4+CD25+Tregs含量,实时荧光定量聚合酶链反应(RT-FQ-PCR)分析MG患者与HCs外周血CD4+CD25+Tregs中FoxP3 mRNA的表达.结果 MG患者外周血CD4+CD25+ Tregs占CD4+T细胞含量与HCs比较无统计学差异(P＞0.05).MG患者外周血FoxP3+CD4+CD25+ Tregs含量及FoxP3 mRNA表达量与HCs比较均显著性降低(P＜0.05);胸腺切除的MG患者与未经胸腺切除的MG患者外周血FoxP3+CD4+CD25+ Tregs含量及FoxP3mRNA表达量无统计学差异(P＞0.05).结论 MG患者外周血CD4+CD25+ Tregs数量正常,但其表面分子FoxP3的表达下调,这种CD4+CD25+ Tregs亚群的异常发现有助于深入阐明MG的免疫发病机制.     

重症肌无力患者外周血CD4+T细胞OX40的表达及作用机制研究

目的 分析重症肌无力(MG)患者外周血CD4+T细胞协同刺激分子OX40表达及其对FoxP3+CD4+CD25+调节性T细胞(Treg)的调控作用,初步探讨OX40在MG免疫学发病中的作用机制.方法 以流式细胞技术检测42例MG患者及38名健康对照的外周血OX40+CD4+T细胞、FoxP3+CD4+CD25+Treg表达水平,比较OX40表达在MG患者不同临床疾病状态、Osserman分型、临床绝对评分、胸腺病理类型等情况下的差异,并分析OX40对FoxP3+CD4+CD25+Treg细胞的影响.结果 (1) MG患者外周血OX40+CD4+T细胞占淋巴细胞百分比高于健康对照组(P<0.01).(2)MG患者OX40+CD4+T细胞百分比在发作或加重期高于缓解期(P＜0.05);在临床绝对评分呈中、重度患者OX40+CD4+T细胞百分比高于轻度患者(均P＜0.05);Osserman Ⅱ、Ⅳ型患者OX40+CD4+T细胞百分比高于Ⅰ型患者(均P＜0.05);胸腺增生及胸腺瘤患者OX40+CD4+T细胞百分比高于胸腺正常患者(P＜0.05,P＜0.01).(3)MG患者外周血OX40+CD4+T细胞百分比与FoxP3+CD4+CD25+Treg细胞百分比呈负相关(r=-0.843,P=0.01).结论 协同刺激分子OX40参与MG发病,可能通过抑制FoxP3+CD4+CD25+Treg细胞生成发挥作用.     

辅助性T细胞及其细胞因子在重症肌无力中的作用

目的探讨辅助性T细胞及其相关细胞因子在全身型MG患者急性期发病中的作用。方法采用流式细胞术检测33例全身型MG患者和34例健康对照组外周血中Tfh细胞亚群CXCR5~+CD4~+T、CD45RO~+CXCR5~+CD4~+T、CD45RA~+CXCR5~+CD4~+T、ICOS~+CXCR5~+CD4~+T和PD-1~+CXCR5~+CD4~+T细胞占CD4~+T细胞的比例。采用流式液相多重蛋白定量(cell based assay,CBA)技术检测MG组及对照组血清中IL-17A、IFN-γ、IL-4、IL-21的含量。应用ELISA技术检测MG组及对照组血清中IL-22的含量。根据QMGs(the quantitative myasthenia gravis score,QMGs)对纳入研究的MG患者进行评分,QMGs反映了MG患者的病情严重程度。结果 MG组外周血中的循环Tfh细胞(ICOS~+CXCR5~+CD4~+T和PD-1~+CXCR5~+CD4~+T)较对照组增高(P=0.016,P0.001),且PD-1~+CXCR5~+CD4~+T细胞与MG患者病情严重程度正相关(r=0.405,P=0.019)。MG组血清IL-21、IL-17A、IFN-γ的含量较对照组升高,有统计学意义(P=0.007,P=0.016,P=0.007);MG组血清IL-4的含量较对照组略有增多,IL-22含量较对照组略有减少,但均无统计学意义。MG组IL-4含量QMGs呈负相关,差异具有显著性(r=-0.393,P=0.024)。结论 MG急性期ICOS~+和PD-1~+的循环Tfh细胞可能促进MG发病;IL-21、IFN-γ、IL-17A同样可能促进MG发病;IL-4可能对MG有保护作用。     

重症肌无力患者外周血Foxp3和CD152表达变化及其相关性分析

目的研究重症肌无力(MG)患者经全胸腺切除治疗外周血中调节性T细胞(CD4~+ CD25~+ Treg)中Foxp3及CD152(CTLA-4)的表达情况。方法采集重症肌无力经手术切除胸腺患者50例术前和术后6个月外周血为实验组,对照组为25例健康志愿者的外周血。应用流式细胞分析方法检测患者手术前后和健康志愿者外周血中的调节性T细胞Foxp3及CD152(CTLA-4)的表达情况。结果患有MG患者术前外周血中调节性T细胞Foxp3及CD152(CTLA-4)表达水平与对照组相比显著降低(P0.05);全胸腺切除6个月后CD4~+ CD25~+ Foxp3~+ Treg细胞及CD152(CTLA-4)表达比例与手术前比较升高(P0.05),与健康对照组比较水平低(P0.05);调节性T细胞中Foxp3表达水平与CD152(CTLA-4)表达水平呈现一定的正相关性(P0.001)。结论重症肌无力患者外周血调节性T细胞中Foxp3和CD152(CTLA-4)表达水平较低,手术治疗能够明显提高Foxp3及CD152(CTLA-4),然而与正常人比较还不能达到正常的水平,为重症肌无力发病机制与胸腺切除治疗提供了理论依据。     

眼肌型及全身型重症肌无力患者外周血T淋巴细胞Fas的表达

目的 探讨Fas介导的细胞凋亡与眼肌型(ocular myasthenia gravis,OMG)及全身型重症肌无力(generalized myasthenia gravis,GMG)发病的关系.方法 采用流式细胞技术检测4例OMG、13例GMG患者及13例健康对照组外周血淋巴细胞中CD4、CD8及Fas的表达.结果 OMG、GMG组与对照组外周血T淋巴细胞表面CD4、CD8分子表达的差异无统计学意义(P>0.05).GMG组与对照组外周血T淋巴细胞中Fas+细胞比例的差异有统计学意义(41.72%±8.73%、31.22%±13.00%,P:0.017).GMG组与对照组Fas表达增高者比例的差异有统计学意义(61.5%、15,4%,P=0.041).Fas表达增高的GMG患者病情较重.病程较长.胸腺瘤发生率较高.OMG与GMG组外周血T淋巴细胞中Fa8+、CD4+Fas+、CD8+Fas+细胞比例差异无统计学意义(P>0.05).结论 GMG患者外周血T淋巴细胞中Fas的表达升高,OMG与GMG患者外周血T淋巴细胞中Fas的表达无显著差异,二者可能同属一种系统性疾病.     

重症肌无力胸腺淋巴细胞亚群表型的变化

目的　研究重症肌无力 (myastheniagravis ,MG)患者胸腺的T、B淋巴细胞亚群表型 ,并分析与其外周血的相关性。方法　应用免疫荧光标记技术 ,经流式细胞仪分析 ,检测了 59例MG患者 ,包括 30例伴胸腺病变患者外周血的淋巴细胞亚群表型。另外 ,对 8例MG患者的胸腺和外周血经体外培养后进行检测。结果　 ( 1)MG患者外周血辅助性T细胞 (Th ,CD4 )异常增高 ,病程 6个月以内、伴胸腺增生者Th细胞均明显增多 ;( 2 )MG胸腺和外周血中经乙酰胆碱受体 (AChR)刺激后活化的Th细胞 (CD4 CD2 5 )、CD5-B细胞 (CD5- CD19 )明显增多 ,且外周血CD5-B细胞与自身血清乙酰胆碱受体抗体 (AChRAb)滴度显著相关 (P <0 .0 1) ,胸腺摘除术 (Tx)后 ,MG外周血CD4 CD2 5 、CD5- CD19 细胞均有所减少。结论　MG患者胸腺存在着异常的AChR特异应答性T、B淋巴细胞亚群表型 ,尤其以活化的Th细胞为著 ;CD5-B细胞的产生可能与MG密切相关。     

白细胞介素-7/CD127信号通路对重症肌无力患者CD8+T细胞的调控作用

目的研究重症肌无力(MG)患者白细胞介素-7(IL-7)/CD127信号通路对CD8+T细胞的调控作用。方法收集2017—2020年在南阳市中心医院神经内科就诊的初治MG患者57例(MG组), 同时入组健康对照者35名(健康对照组), 采集两组受试者的外周血分离血浆和外周血单个核细胞, 采用酶联免疫吸附试验(ELISA)检测血浆中IL-7和可溶型CD127水平, 用流式细胞术检测CD8+T细胞中膜型CD127的表达比例, 分析上述指标在不同性别和发病年龄、有无胸腺瘤、不同Osserman分型之间的差异及与定量重症肌无力(QMG)量表评分的相关性。纯化MG患者CD8+T细胞, 使用重组人IL-7(5 μg/L)刺激培养, 比较可溶型CD127和膜型CD127的水平变化, ELISA法检测培养上清中穿孔素、颗粒酶B、干扰素-γ、肿瘤坏死因子-α(TNF-α)水平;采用实时荧光定量聚合酶链反应法检测CD8+T细胞中免疫检查点分子mRNA表达量。结果 MG组血浆IL-7水平高于健康对照组[(293.4±74.7)pg/ml比(233.8±70.8)pg/ml, t=3.78, P<0.0...     

重症肌无力患者的心肌酶及心电图分析

目的　探讨重症肌无力 (MG)患者的心脏损害。方法　对 1 0 3例MG患者空腹取血查心肌酶 ,心电图检查。结果　 1 0 3例MG患者中心肌酶异常率 2 6 2 % (2 7/ 1 0 3) ,心电图异常率 2 3 3 % (2 4 / 1 0 3)。伴胸腺瘤的MG患者与不伴胸腺瘤的MG患者之间的心肌酶异常率及心电图异常率均有显著性差异 (P <0 0 5)。眼肌型患者与全身型患者之间的心肌酶异常率及心电图异常率均无显著性差异 (P >0 0 5)。结论　MG患者伴有心脏损害 ,尤其伴胸腺瘤的MG患者。心肌酶及心电图检查可提示MG患者的心脏损害。     

重症肌无力患者外周血T、B淋巴细胞Bcl-2的表达

目的　探讨重症肌无力 (MG)患者外周血单个核细胞Bcl 2蛋白表达及其临床意义。方法　以流式细胞仪双标记免疫荧光方法测定 4 7例临床确诊的MG患者外周血T、B淋巴细胞Bcl 2蛋白表达和CD3 T细胞Bcl 2蛋白表达的平均荧光强度 (MFI)。结果　 ( 1)MG组外周血CD3 、CD4 、CD8 T淋巴细胞和CD19 细胞Bcl 2蛋白表达明显高于对照组 (P <0 .0 1) ,CD3 T细胞蛋白表达Bcl 2的MFI( 0 .572± 0 .177)亦明显高于对照组 ( 0 .170± 0 .147) (P <0 .0 1)。 ( 2 )MG组外周血CD3 、CD4 、CD8 T淋巴细胞及CD19 细胞的Bcl 2蛋白表达与年龄无明显相关 ,而与临床严重程度绝对评分密切相关 (r=0 .63、0 .65、0 .61、0 .78,P <0 .0 5)。CD3 T细胞蛋白表达的MFI与MG患者病程相关密切 (r=0 .62 ,P <0 .0 1)。 ( 3)免疫抑制治疗后MG组临床严重程度绝对评分与淋巴细胞亚群Bcl 2蛋白表达、CD3 T细胞蛋白表达的MFI同步地较治疗前有明显下降 (P <0 .0 1)。结论　外周血淋巴细胞Bcl 2蛋白异常表达对MG发病及临床症状有重要作用。     

重症肌无力胸腺基质淋巴细胞生成素表达与CD4~+CD25~+Foxp3~+Treg细胞表型的研究

目的探索重症肌无力患者胸腺基质淋巴细胞生成素(TSLP)表达水平与CD4+CD25+Foxp3+调节性T细胞(Treg)表型的相关性。方法 MG组(16例经胸腺切除的MG患者)及对照组(23例先天性心脏病心脏手术后患者)取外周血单个核细胞,经CD4+CD25+抗体表面染色后加入破膜剂孵育,以Foxp3+抗体行胞内染色,以流式细胞技术检测CD4+CD25+Foxp3+Treg/CD4+T细胞比率;同时取两组患者对应的切除胸腺组织,以免疫组织化学法检测TSLP表达水平,并进行两组间比较;以Logistic回归分析方法分析TSLP阳性表达的Hassall小体计数与Treg细胞之间的相关性。结果CD4+CD25+/CD4+T细胞比率MG组〔(6.24±0.62)%〕与对照组〔(6.56±0.65)%〕无统计学差异(P>0.05),MG组CD4+CD25+Foxp3+Treg/CD4+T细胞比率〔(3.82±0.49)%〕较对照组〔(5.73±0.56)%〕明显降低(P<0.01);与对照组比较,MG组患者胸腺TSLP阳性面积大,染色深,且TSLP阳性的Hassall小体数目(6.81±2.17)明显低于对照组(18.87±3.06)(P<0.01)。MG组TSLP阳性表达的Hassall小体计数与Treg细胞表达量之间呈线性相关(R2=0.158,F=13.42,P<0.01)。结论 MG患者TSLP表达不足与胸腺Treg细胞发育过程中CD4+CD25+Foxp3+表型的表达缺陷呈正相关。     

Programmed Death-1: from gene to protein in autoimmune human myasthenia gravis

The key role of an inhibitory receptor, Programmed Death-1, has been evaluated in 273 patients with autoimmune myasthenia gravis. At the genetic level, SNP's genotyping showed no significant association to the disease. Gene expressions in patients were not different from that in controls. Interestingly, at the cell-surface protein level, there were significant elevated levels of PD-1 on T cells and its ligand PD-L1 on monocytes in the patients compared to controls. However, we could not demonstrate any secreted soluble forms of PD-1 among the patients and controls. Thus, our study shows PD-1 might have a natural regulatory property behind MG.     

Elevated cerebrospinal fluid CD4/CD8 T cell ratio in myasthenia gravis

The proportions of CD2+, CD4+ and CD8+ lymphocytes were determined with the 3-layer indirect immunoperoxidase technique in the cerebrospinal fluid (CSF) of 31 patients with myasthenia gravis (MG) and 21 control subjects without autoimmune or central nervous system (CNS) diseases. None of the MG patients were using immunosuppressive drugs and all were thymectomized shortly after CSF sampling. Analysis of the reference population showed that the percentage of CD4+ lymphocytes and accordingly the CD4+/CD8+ T cell ratio is normally higher in CSF than in peripheral blood (PB). Compared to the controls, the mean percentage of CD4+ lymphocytes and the mean CD4+/CD8+ ratio in CSF were significantly higher in MG patients. In addition, the CD4+/CD8+ ratio was elevated in the CSF of 15 MG patients (48%) as a result of an elevation in the proportion of CD4+ and/or a decrease in CD8+ T cells. Among MG subjects the mean proportion of CD4+ lymphocytes was higher in the CSF of patients with also an elevated number of enlarged stimulated lymphoid cells in their CSF, which implies that these lymphocytes are often of the CD4+ phenotype. The percentage of CD4+ T cells in CSF was significantly higher in MG patients with a hyperplastic thymus or a thymoma than in those with an involuted thymus. Neither in MG patients nor in the reference population could an association be observed between CSF and PB lymphocyte subsets. In the controls this suggests that immunologic events of the CNS are normally not directly reflected in PB.(ABSTRACT TRUNCATED AT 250 WORDS)     

Thymic abnormalities in patients with myasthenia gravis

Thymic abnormalities were first noticed at autopsies of patients with myasthenia gravis (MG) more than 100 years ago. The thymus is believed to play an important role in the pathogenesis of MG, an autoimmune disease mediated by antibodies against the acetylcholine receptor (AChR) of skeletal muscles. Production of these antibodies in B cells is T cell dependent. T cells potentially specific for AChR are probably generated in the thymus via nontolerogenic thymopoiesis by an aberrant function of thymic epithelial cells. However, generation of these AChR-specific T cells is not the cause of MG, because these cells are also found in healthy individuals. The pathogenetic step in MG involves the activation of these potentially AChR-specific T cells; this activation is the trigger to develop the disease and a therapeutic target. The intra-thymic activation of AChR-specific T cells is probably limited to particular types of MG patients: those with early-onset MG in whom the thymus exhibits lymphofollicular hyperplasia (TLFH) and a few patients in whom MG is associated with a thymoma. The majority of thymomas and atrophic thymuses of patients with late-onset MG, an increasingly common condition, do not exhibit this T cell-activation process. In this paper, we review the available literature on thymic changes (TLFH, thymoma, and atrophic thymus) and the relationship of these changes to the pathogenesis of MG.     

晚发型重症肌无力临床研究

目的探讨晚发型重症肌无力(Myasthenia gravis,MG)患者的临床特点。方法回顾性研究40例晚发型MG的临床特点并与早发型MG比较。结果晚发型MG患者男/女比例高于早发型MG,为1.22:1。晚发型MG的症状由眼肌受累演变至全身症状(占67.5%)显著高于早发型MG(占38.7%)。晚发型MG的肌无力程度较早发型MG肌无力程度严重,而且血清乙酰胆碱受体(acetylcholine receptor,AchR)抗体阳性率及抗体水平均显著低于早发型MG低,但Titin抗体阳性率及抗体水平却显著高于早发型MG。胆碱酯酶抑制剂对晚发型MG的疗效不如早发型MG。结论晚发型MG是一个免疫异质性的MG亚群,它的临床表现以及血清免疫学特点不同于早发型MG。     

Antigen-specific T-cell activation in hyperplastic thymus in myasthenia gravis

In order to determine whether antigen-specific T-cell activation by dendritic cells (DCs) is accelerated in thymuses exhibiting lymphofollicular hyperplasia (TLFH) among patients with early-onset myasthenia gravis (EOMG), we investigated the expression levels of phosphorylated protein kinase C (PKC)theta and the local relationship between the presence of phosphorylated PKCtheta and the homing receptor CD44 or CD83, a marker for mature DCs, in samples taken from EOMG patients with early improvement following thymectomy, in remnant thymuses from late-onset MG patients, and in non-MG control thymuses. Antigen-specific T-cell activation was markedly accelerated in TLFH from EOMG patients. Activated T cells and adjacent DCs appeared to be components of a CD44(high) cell population circulating from the blood to the thymus. Although there is no convincing evidence that thymectomy is of benefit in MG, in some EOMG patients with early improvement following thymectomy, blockade of CD44-associated circulation mechanisms is probably the cause for the early benefits of thymectomy and is a potential alternative to thymectomy.     

Clinical and immunological differences between early and late-onset myasthenia gravis in Japan

Immunological characteristics of myasthenia gravis (MG) with late-onset have not been fully elucidated. We examined several autoantibodies and HLA-DRB1 genotyping in 260 Japanese MG patients. Sixty-two MG patients had thymoma. The others were divided into early-onset and late-onset groups separated by an age of 50 years. The ocular form was more frequent in late-onset compared to early-onset group. Seropositivity of anti-muscle-specific tyrosine kinase antibody was 2-3% in acetylcholine receptor-seronegative patients. HLA-DRB1 genotyping failed to detect statistical differences in specific alleles between each group and healthy controls. The immunological profiles in late-onset MG were different from early-onset in Japan.     

The PD-1/PD-L pathway is up-regulated during IL-12-induced suppression of EAE mediated by IFN-gamma

Experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), is mediated by autoantigen-specific T-helper1 (Th1) cells. IL-12, an inducer of Th1 cell development, exerts immunomodulatory effects in EAE. Programmed death-1 (PD-1) and PD-1 ligand (PD-L), new members of the B7 superfamily of costimulatory molecules, play a critical role in regulating EAE. Whether the interaction of IL-12 and the PD-1/PD-L pathway regulates EAE is unclear. We have previously shown that IL-12 suppresses EAE induced by MOG35-55 in C57BL/6 mice, but not in IFN-gamma-deficient mice, suggesting that IFN-gamma is required for the inhibitory effects of IL-12 on EAE. In the current study, PD-L1 expression is up-regulated following IL-12 treatment in wild-type mice, but not in IFN-(-deficient EAE mice. Similarly, IL-12 induces IFN-gamma and PD-L1 expression in cultured MOG-specific T cells from wild-type mice but not from IFN-gamma-deficient mice. Furthermore, PD-L1 expression increased specifically in CD11b+ antigen presenting cells (APCs) after IL-12 administration. These data suggest that one mechanism of IL-12 suppression of EAE is mediated by PD-1/PD-L signaling downstream of IFN-gamma induction in CD11b+ APCs. The regulation of PD-1/PD-L1 may have potential therapeutic effects for EAE and MS.     

The majority of infiltrating CD8 T lymphocytes in multiple sclerosis lesions is insensitive to enhanced PD-L1 levels on CNS cells

Central nervous system (CNS) cells locally modulate immune responses using numerous molecules that are not fully elucidated. Engagement of programmed death-1 (PD-1), expressed on activated T cells, by its ligands (PD-L1 or PD-L2) suppresses T-cell responses. Enhanced CNS PD-1 and PD-L1 expression has been documented in inflammatory murine models; however, human CNS data are still incomplete. We determined that human primary cultures of astrocytes, microglia, oligodendrocytes, or neurons expressed low or undetectable PD-L1 under basal conditions, but inflammatory cytokines significantly induced such expression, especially on astrocytes and microglia. Blocking PD-L1 expression in astrocytes using specific siRNA led to significantly increased CD8 T-cell responses (proliferation, cytokines, lytic enzyme). Thus, our results establish that inflamed human glial cells can express sufficient and functional PD-L1 to inhibit CD8 T cell responses. Extensive immunohistochemical analysis of postmortem brain tissues demonstrated a significantly greater PD-L1 expression in multiple sclerosis (MS) lesions compared with control tissues, which colocalized with astrocyte or microglia/macrophage cell markers. However, more than half of infiltrating CD8 T lymphocytes in MS lesions did not express PD-1, the cognate receptor. Thus, our results demonstrate that inflamed human CNS cells such as in MS lesions express significantly elevated PD-L1, providing a means to reduce CD8 T cell responses, but most of these infiltrating immune cells are devoid of PD-1 and thus insensitive to PD-L1/L2. Strategies aimed at inducing PD-1 on deleterious activated human CD8 T cells that are devoid of this receptor could provide therapeutic benefits since PD-L1 is already increased in the target organ.     

Subsets of lymphoid cells in blood and thymus in myasthenia gravis : Monoclonal Antibody Analysis

Lymphoid cell subpopulations in peripheral blood and thymus were analyzed in patients with myasthenia gravis (MG) using monoclonal antibodies. The proportion of lymphocytes of T lineage (OKT 3 +, OKT 4 +, OKT 8 + cells) in peripheral blood of 11 MG patients, was significantly decreased in comparison with controls, but the ratio of OKT 4+/OKT 8+ cells was not different. Thymus cells were studied in 9 patients. The percentage of OKIa 1 + cells was significantly higher in MG thymus than in control thymus (P < 0.0005). There were no significant differences in the proportions of T lymphocyte subsets between MG and control thymuses.     

Changes in lymphocyte subsets in myasthenia gravis: correlation with level of antibodies to acetylcholine receptor and age of patient.

We report a detailed analysis of the subsets of lymphocytes in patients with myasthenia gravis (MG). There was a slight, nonsignificant increase in the level of CD5+ B lymphocytes among MG patients as compared with normal controls. The proportion of CD5+ T cells in MG was similar to that in controls. However, whereas age had no effect on the level of these cells in normal individuals, a significant age-related decrease of these cells was present in MG patients. The proportion of double-positive CD4+CD8+ T cells was significantly increased in MG. The level of the CD29+CD4+ (helper-inducer) subset was significantly higher in MG patients than in controls. There was no correlation between the titer of autoantibodies to acetylcholine receptor and the level of either CD29+CD4+ T cells or CD5+ B cells among MG patients. The only T-cell subset that correlated with the autoantibody titer was the CD45RA+CD4+ (suppressor-inducer) subset of CD4+ T cells.