Th1 and Th2 subsets: paradigms lost?

The T helper 1 (Th1)/Th2 model has provided a valuable framework to investigate and explain many immune reactions and now pervades current thinking on the regulatory role of T cells. However, individual T cells and clones display remarkable diversity in their cytokine profiles, collectively forming a continuous spectrum in which Th1 and Th2 cells may be only two of the possible extreme phenotypes. For these reasons, Anne Kelso argues that cytokine-producing T cells cannot be classified into discrete subsets.     

CD4+ T helper cells and regulatory T cells in active lupus nephritis: an imbalance towards a predominant Th1 response?

The objective of this study was to evaluate the frequency of CD4⁺ T cell subsets in peripheral blood mononuclear cells (PBMC), urine and renal tissue from patients with lupus nephritis (LN). PBMC and urinary cells were collected from 17 patients with active LN, 20 disease controls (DC) with primary glomerulonephritis and 10 healthy controls (HC) and were analysed by flow cytometry with markers for T helper type 1 (Th1), Th2, Th17 and regulatory T cells (T_reg) cells. T cell subsets were assessed by immunohistochemistry from LN biopsy specimens from 12 LN patients. T cell subtypes in PBMC were re‐evaluated at 6 months of therapy. CD4⁺ T cells were decreased in PBMC in LN compared with DC and HC (P = 0·0001). No differences were observed in urinary CD4⁺ T cell subsets between LN and DC. The frequency of urinary Th17 cells was higher in patients with non‐proliferative than in proliferative LN (P = 0·041). CD3⁺ and T‐box 21 ( ) cells were found in glomeruli and interstitium of LN patients, while forkhead box protein 3 (FoxP3), retinoid‐related orphan receptor gamma (ROR‐γ) and GATA binding protein 3 (GATA‐3) were present only in glomeruli. Th1 cells in PBMC were correlated negatively with urinary Th1 cells (Rho = –0·531; P = 0·028) and with T_bet in renal interstitium (Rho = –0·782; P = 0·004). At 6 months, LN patients showed an increase in Th17 cells in PBMC. In conclusion, the inverse association between Th1 cells from PBMC and urinary/renal tissue indicate a role for Th1 in LN pathophysiology. Urinary Th17 cells were associated with less severe LN, and Th17 increased in PBMC during therapy. Urinary CD4⁺ T cells were not different between LN and DC.     

Interleukin-18 and Interleukin-1β: Two Cytokine Substrates for ICE (Caspase-1)

This special article deals with the role of processing enzymes in the generation of bioactive cytokines, particularly IL-1 and the novel cytokine IL-18, which was formerly called IFN-inducing factor (IGIF). The classical pathways of cytokine processing are described, as well as the importance of alternative cleavage enzymes. The topic of this review also concerns the biology of IL-18. The regulation of IL-18 production, the IL-18 receptor complex, and the biological effects of this novel cytokine are described.     

Effect of NF-κB Inhibitor Aurothiomalate on Local Inflammation in Experimental Th1- and Th2-Type Immune Response

We compared the effect of NF-kappaB inhibitor aurothiomalate and voltaren on local inflammation in different types of immune response. Both substances reduced edema caused by sheep erythrocytes (Th1-type immune response) and local immediate-type hypersensitivity response induced with ovalbumin (Th2-dependent response). The anti-inflammatory effects of aurothiomalate were similar to those of voltaren during Th1-type immune response.     

Glomerulonephritis,Th1 and Th2: what's new?

Glomerulonephritis (GN), the major worldwide cause of chronic renal disease and renal failure, shows a wide spectrum of histological patterns, severity of injury and clinical outcomes that may be related to the nature of the nephritogenic immune response. In the majority of cases, there is evidence of a central role for cognate immunity in the initiation of human GN and contributions of both humoral and cellular effector mechanisms have been demonstrated in both humans and in animal models. T helper cell subsets are known to activate different immune effector mechanisms which influence disease outcomes in infectious and autoimmune diseases and evidence is now accumulating that Th1 and Th2 subsets direct diverging effector pathways that lead to different patterns and severity of glomerular injury in GN. Th1-predominant responses appear to be associated strongly with proliferative and crescentic forms of GN that result in severe renal injury, while Th2 responses are associated with membranous patterns of injury. The challenge remains to understand fully the relevance of T helper cell subset responses to the spectrum of human GN and to apply this new knowledge to the development of more potent and selective therapeutic strategies.     

Infection of Human Dendritic Cells by Dengue Virus Activates and Primes T Cells Towards Th0‐Like Phenotype Producing Both Th1 and Th2 Cytokines

Dengue viruses (DV) infection is an important public health issue all over the world. Although the pathogenesis remains unclear, the overwhelmingly triggered immune responses have been consistently observed. Recently, we and other researchers demonstrated that the natural hosts for DV are dendritic cells (DC), the primary sentinels of immune system. In light of the significance of T cells in dengue virus pathogenesis, here, we examine the possible consequences of DC‐T cell interaction that is supposed to be happening in lymphoid tissues after infection. We showed that DV‐infected DC induced the interacting T cells to proliferate, to produce interleukin‐2 as well as to express activation markers on cell surface. Compared to mock‐infected DC, the infection of DC by DV also induced T cells to produce interleukin‐4, interleukin‐10 and interferon‐gamma, a cytokine pattern suggesting Th0 phenotype. Such an effect was either totally abolished or greatly reduced when DV were pre‐inactivated with heat or ultraviolet before infection. In addition, we demonstrated that such a Th0 phenotype shift of T cells was affected neither by different dosages of viruses that infected DC nor by different durations of DC‐T cell interaction. Our results provide a basic support for clinical observations and may be of help in understanding the pathogenesis of DV infection.     

Effects of the Overall Alkaloid of a Traditional Chinese Medicine “Tongbiling” on the Cytokine Expression in Th1 and Th2 Cells of Rheumatoid Arthritis and Their Signaling Pathway

Rheumatoidarthritis(RA)isachronicautoimmunedis easecharacterizedbychronicinflammatoryofsynovium andsystemicvasculitis.Tcells,especiallyCD4 Tcells (Th)whicharethemajorsubsetsofcellsin…     

Th1、Th2T细胞及其细胞因子在自身免疫性糖尿病中的作用

Ⅰ型糖尿病是T细胞介导的自身免疫性疾病,Th细胞亚群在疾病的发生过程中起了一定的作用。其中致病性免疫过程是由T细胞亚群Th1介导的,而TH2细胞亚群则是介导保护性免疫反应的。Th1型细胞因子(IL-2.IFN)通过直接促进细胞凋亡和/或上调选择性粘附分子的表达,以及Th1细胞因子可促进自身反应性T细胞在胰腺的浸润,二者均导致β细胞的破坏;Th1细胞介导的针对谷氨酸脱羧酶(GAD)的自身免疫反应增强,并通过分子内和分子间传导的机制转导至其他β细胞。Th1和Th2亚群实质上是机体在特异性抗原刺激下,Th细胞发生相对优势转化的结果。Th细胞的优势转化具有可塑性,对Th1或Th2型细胞因子或抗细胞因子单抗的研究,将为临床上自身免疫性糖尿病的治疗开辟新的途径。     

TSST-1 induces Th1 or Th2 differentiation in naïve CD4+ T cells in a dose- and APC-dependent manner

Superantigens are potent activators of the immune system, causing a variety of diseases, ranging from food poisoning to septic shock. Here, we examined the effects of different toxic shock syndrome toxin 1 (TSST‐1) concentrations on the activation, proliferation and synthesis of interferon‐γ (IFN‐γ) and interleukin‐4 (IL‐4) in purified naïve human CD4⁺ T cells in a serum‐free in vitro system. TSST‐1 given in low doses (1–10 pg/ml) generates a pronounced T helper 2 (Th2)‐like cytokine profile, characterized by elevated IL‐4‐expressing T‐cell populations and reduced IFN‐γ‐producing populations, whereas higher doses (100 pg/ml) induce a Th1‐like profile, with increased expression of IFN‐γ and reduced expression of IL‐4. These patterns were even more pronounced by adding exogenous cytokines like IL‐12 and IL‐4 and by the type of antigen‐presenting cells (APCs). Thus, B cells induced Th2 shifts, whereas monocytes favoured Th1 induction. Moreover, IL‐12 in conditions with B cells counteracted their Th2 bias. Interestingly, in purified naïve T‐cell cultures, containing a small population of HLA‐DR⁺ T cells, Th1/Th2 differentiation can be induced by TSST‐1 too. There, Th‐cell polarization is strongly dependent on TSST‐1 concentration, indicating that this is a key parameter in regulating the differentiation of T cells. In conclusion, our data show that Th1/Th2 differentiation of TSST‐1‐stimulated naïve T cells is controlled by the type of APCs, and in APC‐depleted cultures, it depends on the presence of HLA‐DR⁺ cells and TSST‐1 concentration.     

LSD1影响CD4~+T细胞Th1/Th2分化的机制研究

目的探讨LSD1的脱甲基酶活性对人外周血CD4+T细胞Th1/Th2分化格局的影响及其分子机制。方法 anti-CD3/28刺激活化人外周血CD4+T细胞48 h后,shLSD1和反苯环丙胺(TCP)抑制LSD1的表达,流式细胞术检测细胞内细胞因子IFN-γ、IL-4的表达情况;逆转录聚合酶链式反应(RT-PCR)和实时荧光定量PCR(RQ-PCR)检测不同浓度TCP对T细胞IFN-γ、IL-4、Tbet mRNA表达的影响;Western blot观察LSD1、T-bet、STAT1和pSTAT1蛋白表达情况。结果 shLSD1和TCP组细胞IFN-γ+T细胞比例[(26.13±1.89)%和(27.01±1.18)%]明显高于对照组[(14.67±0.65)%,(P0.05)],而IL-4+T细胞比例与对照组无显著变化(P0.05);RT-PCR检测显示,shLSD1和TCP组IFN-γmRNA表达明显高于对照组(P0.05),IL-4基因表达则没有改变(P0.05);转染shLSD1或TCP处理引起T-bet、pSTAT1表达明显高于对照组(P0.05),而STAT1表达无明显变化(P0.05)。结论下调LSD1表达可以促进人CD4+T细胞向Th1方向分化,对Th2方向细胞无影响。其分子机制涉及T-bet/STAT1信号通路。     

Th1/Th2与慢性乙型肝炎

慢性乙型肝炎发病机制复杂 ,与机体的免疫状态密切相关 ,CD4 + Th细胞是机体的重要调节细胞 ,根据其产生细胞因子的不同分为Th1和Th2亚型 ,分别参与调节细胞免疫和体液免疫 ,Th1和Th2可相互调节 ,影响免疫应答的格局 ,Th1 Th2在多种感染性疾病中发挥重要作用 ,慢性乙肝患者存在Th1 Th2失衡 ,本文就Th1 Th2与慢性乙肝的关系研究进展进行简述。     

淫羊藿总黄酮(EF)对老龄大鼠Th1、Th2、Th3细胞的调节作用

目的：探讨淫羊藿总黄酮（EF）对衰老大鼠脾淋巴细胞Th1、Th2、Th3各类细胞因子的调节作用.方法：采用流式细胞仪,监测比较老龄大鼠脾脏淋巴细胞凋亡率;采用Th1、Th2、Th3 cDNA芯片,分别检测正常青年组（YC）、老龄大鼠组（OM）、EF组、NF-KB阻断剂组（PDTC）、PDTC＋EF组的Th1、Th2、Th3,各类细胞因子信号差异表达.结果：①老龄大鼠普遍存在淋巴细胞过度凋亡现象,EF可显著抑制这种过度凋亡状态.②YC组,Th1、Th2、Th3类细胞因子之间处于平衡状态（P＞0.05）;OM组Th1、Th2、Th3类细胞因子表达比YC组增高,呈Th2、Th3类细胞因子优势应答（P＜0.05）.③EF组Th1、Th2、Th3类细胞因子均较OM组明显降低（P＜0.05）,其趋势与YC组近似,并且Th1、Th2、Th3类细胞恢复平衡.④NFKB通路抑制后（PDTC组）,Th1、Th2、Th3类细胞因子平衡失调,Th2优势更加明显（P＜0.05）;而PDTC＋EF组,Th1、Th2、Th3各组表达值则较PDTC组下调,其组内Th1和Th2也重新达到一种相对平衡状态.结论：老龄大鼠脾淋巴细胞过度凋亡,Th1、Th2、Th3类细胞因子分泌增高,Th2、Th3类细胞因子优势应答;EF可以抑制淋巴细胞过度凋亡,校正老龄大鼠Th1、Th2、Th3类细胞因子之间的比例失衡,重塑Th1-Th2-Th3细胞免疫调节网络的良性平衡.     

Graves'病患者Th1/Th2免疫应答及性激素对Th1/Th2的影响

Graves'病(GD)是最常见的自身免疫性甲状腺疾病(AI-TD),其发病机理以体液免疫异常为大家所熟知,但细胞因子在GD中的发病作用越来越受到国内外学者的重视,研究的焦点主要侧重于Th1/Tb2细胞平衡紊乱.GD及其他自身免疫性疾病女性显著高发,提示性激素是影响机体免疫功能的重要因素.本文就近年来国内外对GD患者Th1/Th2免疫应答的研究及性激素对Th1/Th2平衡的影响作一综述.     

Th1／Th2与慢性乙型肝炎

慢性乙型肝炎发病机制复杂，与机体的免疫状态密切相关，CD4^ Th细胞是机体的重要调节细胞，根据其产生细胞因子的不同分为Th1和Th2亚型，分别参与调节细胞免疫和体液免疫，Th1和Th2可相互调节，影响免疫应答的格局，Th1／Th2在多种感染性疾病中发挥重要作用，慢性乙肝患者存在Th1／Th2失衡，本文就Th1／Th2与慢性乙肝的关系研究进展进行简述。     

The kinases MEKK2 and MEKK3 regulate transforming growth factor-β-mediated helper T cell differentiation

Mitogen-activated protein kinases (MAPKs) are key?mediators of the T?cell receptor (TCR) signals but their roles in T helper (Th) cell differentiation are?unclear. Here we showed that the MAPK kinase?kinases MEKK2 (encoded by Map3k2) and?MEKK3 (encoded by Map3k3) negatively regulated transforming growth factor-β (TGF-β)-mediated Th cell differentiation. Map3k2(-/-)Map3k3(Lck-Cre/-) mice showed an abnormal accumulation of regulatory T (Treg) and Th17 cells in the periphery, consistent with Map3k2(-/-)Map3k3(Lck-Cre/-) naive CD4(+) T?cells' differentiation into Treg and Th17 cells with?a higher frequency than wild-type (WT) cells after?TGF-β stimulation in?vitro. In addition, Map3k2(-/-)Map3k3(Lck-Cre/-) mice developed more severe experimental autoimmune encephalomyelitis. Map3k2(-/-)Map3k3(Lck-Cre/-) T?cells exhibited impaired phosphorylation of SMAD2 and SMAD3 proteins at their linker regions, which negatively regulated the TGF-β responses in T?cells. Thus, the crosstalk between TCR-induced MAPK and the TGF-β signaling pathways is important in regulating Th cell differentiation.