CD1-mediated gamma/delta T cell maturation of dendritic cells

The vascular endothelial growth factor (VEGF) receptor fetal liver kinase 1 (flk1; VEGFR-2, KDR) is an endothelial cell-specific receptor tyrosine kinase that mediates physiological and pathological angiogenesis. We hypothesized that an active immunotherapy approach targeting flk1 may inhibit tumor angiogenesis and metastasis. To test this hypothesis, we first evaluated whether immune responses to flk1 could be elicited in mice by immunization with dendritic cells pulsed with a soluble flk1 protein (DC-flk1). This immunization generated flk1-specific neutralizing antibody and CD8+ cytotoxic T cell responses, breaking tolerance to self-flk1 antigen. Tumor-induced angiogenesis was suppressed in immunized mice as measured in an alginate bead assay. Development of pulmonary metastases was strongly inhibited in DC-flk1-immunized mice challenged with B16 melanoma or Lewis lung carcinoma cells. DC-flk1 immunization also significantly prolonged the survival of mice challenged with Lewis lung tumors. Thus, an active immunization strategy that targets an angiogenesis-related antigen on endothelium can inhibit angiogenesis and may be a useful approach for treating angiogenesis-related diseases.     

Type 1 T helper and type 2 T helper cells: Functions,regulation and role in protection and disease

Summary Two very distinct cytokine secretion patterns have been defined amoung murine CD4⁺ T cells. Type 1 helper (T_H1), but not type 2 helper (T_H2), cells produce interleukin (IL)-2, gamma-interferon (IFN-γ) and tumour necrosis factor-β, whereas T_H2, but not T_H1, cells express IL-4, IL-5, IL-6 and IL-10. The different cytokine patterns lead to different functions of the two types of T cell. In general, T_H2 cells are excellent helpers for B-cell antibody secretion, particularly IgE responses. On the other hand T_H1 cells induce delayed-type hypersensitivity reactions. There is general agreement that the different functional subsets of T_H cells arise post-thymically from a common pool of precursors and as a consequence of activation of antigen. However, the factors affecting differentiation of T_H precursors into the T_H1 or T_H2 subsets are still unclear. Mutual cross-regulation between T_H1 (via IFN-γ) and T_H2 (via IL-10) has also been reported. Recently, human T cell clones similar to murine T_H1 and T_H2 cells have been demonstrated. Most allergen- or helminthic antigen-specific CD4⁺ human T cell clones have a T_H2 phenotype, whereas the majority of T-cell clones specific for mycobacterial antigens or antigens responsible for type IV hypersensitivity exhibit a T_H1 phenotype. Human T_H2 clones provide B-cell help for IgE synthesis, whereas most T_H1 clones are cytolytic for antigen-presenting cells, including B lymphocytes. It is highly probable that the selective or preferential activation of CD4⁺ T-cell subsets secreting defined patterns of cytokines is of major importance in determining the class of immune effector function, thus influencing both protection and immunopathology.     

Tumor necrosis factor alpha is a critical component of interleukin 13-mediated protective T helper cell type 2 responses during helminth infection.

In vivo manipulation of cytokine and/or cytokine receptor expression has previously shown that resistance to infection with the caecum-dwelling helminth Trichuris muris is dependent on interleukin (IL)-4 and IL-13 while susceptibility is associated with a T helper cell type 1 (Th1) cytokine response. Using gene-targeted mice deficient in tumor necrosis factor (TNF) receptor signaling and anti-TNF-alpha monoclonal antibody treatment, we have extended these studies to reveal a critical role for TNF-alpha in regulation of Th2 cytokine-mediated host protection. In vivo blockade of TNF-alpha in normally resistant mice, although not altering IL-4, IL-5, or IL-13 production in the draining lymph node, significantly delayed worm expulsion for the duration of treatment. IL-13-mediated worm expulsion in IL-4 knockout (KO) mice was also shown to be TNF-alpha dependent, and could be enhanced by administration of recombinant TNF-alpha. Furthermore, TNF receptor KO mice failed to expel T. muris, producing high levels of parasite-specific immunoglobulin G2a and the generation of a predominantly Th1 response, suggesting that the absence of TNF function from the onset of infection dramatically alters the phenotype of the response. These results provide the first demonstration of the role of TNF-alpha in regulating Th2 cytokine-mediated responses at mucosal sites, and have implications for the design of rational therapies against helminth infection and allergy.     

Phenotypic and functional analysis of CD8(+) T cells undergoing peripheral deletion in response to cross-presentation of self-antigen

Not all T cells specific for autoantigens are eliminated in the thymus, and therefore alternate mechanisms are required to prevent potentially autoreactive T cells from developing into effectors. Adoptive transfer of CD8(+) T cells from influenza hemagglutinin-specific Clone 4 TCR transgenic mice into mice that express hemagluttinin in the pancreatic islets results in tolerance. This is preceded by activation of Clone 4 T cells that encounter antigen cross-presented in the draining lymph nodes of the pancreas. In this report we compare the phenotype, function, and costimulatory requirements of Clone 4 T cells activated by endogenous self-antigen, with Clone 4 T cells stimulated by influenza virus. The cells undergoing tolerance upregulate both CD69 and CD44, yet only partially downregulate CD62L, and do not express CD49d or CD25. Most importantly, they lack the ability to produce interferon-gamma in response to antigen and show no cytolytic activity. Clone 4 T cells disappear after several cycles of division, apparently without leaving the site of initial activation. Surprisingly, despite the fact that such stimulation occurs through recognition of antigen that is cross-presented by a professional antigen-presenting cell, we find this activation is not dependent on costimulation through CD28. These data demonstrate that the recognition by naive CD8(+) T cells of cross-presented self-antigen results in localized proliferation and deletion, without the production of effector cells.     

T辅助淋巴细胞亚群平衡变化与支气管哮喘发病的关系研究

目的研究大鼠哮喘模型以及哮喘患者静脉血中T辅助淋巴细胞(T     

The absence of interleukin 1 receptor-related T1/ST2 does not affect T helper cell type 2 development and its effector function

T1/ST2, an orphan receptor with homology with the interleukin (IL)-1 receptor family, is expressed constitutively and stably on the surface of T helper type 2 (Th2) cells, but not on Th1 cells. T1/ST2 is also expressed on mast cells, which are critical for Th2-mediated effector responses. To evaluate whether T1/ST2 is required for Th2 responses and mast cell function, we have generated T1/ST2-deficient (T1/ST2(-/-)) mice and examined the roles of T1/ST2. Naive CD4(+) T cells isolated from T1/ST2(-/-) mice developed to Th2 cells in response to IL-4 in vitro. T1/ST2(-/-) mice showed normal Th2 responses after infection with the helminthic parasite Nippostrongylus brasiliensis as well as in the mouse model of allergen-induced airway inflammation. In addition, differentiation and function of bone marrow-derived cultured mast cells were unaffected. These findings demonstrate that T1/ST2 does not play an essential role in development and function of Th2 cells and mast cells.     

Interleukin 2, but not other common gamma chain-binding cytokines, can reverse the defect in generation of CD4 effector T cells from naive T cells of aged mice.

Development of effectors from naive CD4 cells occurs in two stages. The early stage involves activation and limited proliferation in response to T cell receptor (TCR) stimulation by antigen and costimulatory antigen presenting cells, whereas the later stage involves proliferation and differentiation in response to growth factors. Using a TCR-transgenic (Tg(+)) model, we have examined the effect of aging on effector generation and studied the ability of gamma(c) signaling cytokines to reverse this effect. Our results indicate that responding naive CD4 cells from aged mice, compared with cells from young mice, make less interleukin (IL)-2, expand poorly between days 3 to 5, and give rise to fewer effectors with a less activated phenotype and reduced ability to produce cytokines. When exogenous IL-2 or other gamma(c) signaling cytokines are added during effector generation, the Tg(+) cells from both young and aged mice proliferate vigorously. However, IL-4, IL-7, and IL-15 all fail to restore efficient effector production. Only effectors from aged mice generated in the presence of IL-2 are able to produce IL-2 in amounts equivalent to those produced by effectors generated from young mice, suggesting that the effect of aging on IL-2 production is reversible only in the presence of exogenous IL-2.     

Alteration of interleukin 4 production results in the inhibition of T helper type 2 cell-dominated inflammatory bowel disease in T cell receptor alpha chain-deficient mice.

T cell receptor alpha chain-deficient (TCR-alpha(-/-)) mice are known to spontaneously develop inflammatory bowel disease (IBD). The colitis that develops in these mice is associated with increased numbers of T helper cell (Th)2-type CD4(+)TCR-betabeta (CD4(+)betabeta) T cells producing predominantly interleukin (IL)-4. To investigate the role of these Th2-type CD4(+)betabeta T cells, we treated TCR-alpha(-/-) mice with anti-IL-4 monoclonal antibody (mAb). Approximately 60% of TCR-alpha(-/-) mice, including those treated with mock Ab and those left untreated, spontaneously developed IBD. However, anti-IL-4 mAb-treated mice exhibited no clinical or histological signs of IBD, and their levels of mucosal and systemic Ab responses were lower than those of mock Ab-treated mice. Although TCR-alpha(-/-) mice treated with either specific or mock Ab developed CD4(+)betabeta T cells, only those treated with anti-IL-4 mAb showed a decrease in Th2-type cytokine production at the level of mRNA and protein and an increase in interferon gamma-specific expression. These findings suggest that IL-4-producing Th2-type CD4(+)betabeta T cells play a major immunopathological role in the induction of IBD in TCR-alpha(-/-) mice, a role that anti-IL-4 mAb inhibits by causing Th2-type CD4(+)betabeta T cells to shift to the Th1 type.     

Imbalance between T helper 1 and regulatory T cells plays a detrimental role in experimental Parkinson’s disease in mice

ObjectiveParkinson’s disease (PD) is a degenerative disorder characterized by steady motor function loss. PD pathogenesis remains inconclusive, but aberrant immune responses might play important roles. We hypothesized that imbalance between T helper (Th) 1 and regulatory T (Treg) cells was essential in experimental PD.MethodsTh1 and Treg cells from the blood of patients with PD and healthy volunteer blood were measured by flow cytometry. Experimental PD was induced in mice by peritoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Experimental PD severity was measured by open field test behavior assessments (distance moved, rearing, and grooming). Mice were administered neutralizing anti-tumor necrosis factor (TNF) α to inhibit Th1 effects. Treg cells were depleted by anti-CD25 neutralizing antibodies or isolated and transferred to experimental PD mice.ResultsPatients with PD had fewer Treg and more Th1 cells than healthy volunteers. Experimental PD mice exhibited fewer Treg and more Th1 cells. Treg cell depletion exacerbated experimental PD, whereas TNFα neutralization attenuated PD in mice. Treg transfer to experimental PD mice reduced PD severity. Mechanistically, anti-TNFα antibody administration and Treg transfer increased Treg and reduced Th1 cell abundance in the brain.ConclusionTh1 and Treg cell imbalance plays an essential role in mouse experimental PD pathogenesis.     

Aberrant blood MALT1 and its relevance with multiple organic dysfunctions,T helper cells,inflammation, and mortality risk of sepsis patients

BackgroundMALT1 is linked with multiple organic dysfunctions, inflammatory storm, and T helper (Th) cell differentiation. Herein, the current study aimed to investigate the correlation of peripheral blood mononuclear cell (PBMC) MALT1 with Th1 cells, Th17 cells, and prognosis of sepsis patients.MethodsIn general, 78 sepsis patients and 40 health controls (HCs) were enrolled. MALT1 expression was detected in PBMCs from all subjects by RT‐qPCR. Besides, Th1 and Th17 cells were measured in PBMCs from sepsis patients by flow cytometry; interleukin 17A (IL‐17A) and interferon gamma (IFN‐γ) were determined in serum from sepsis patients by ELISA.ResultsMALT1 expression was higher in sepsis patients than HCs (p < 0.001). MALT1 expression was positively correlated with Th17 cells (r _s = 0.291, p = 0.038) and IL‐17A (r _s = 0.383, p = 0.001), but not with Th1 cells (r _s = 0.204, p = 0.151) or IFN‐γ (r _s = 0.175, p = 0.125) in sepsis patients. MALT1 expression was positively correlated with APACHE II score (r _s = 0.275, p = 0.015), C‐reactive protein (CRP) (r _s = 0.257, p = 0.023), and sequential organ failure assessment (SOFA) score (r _s = 0.306, p = 0.006) (MALT1 expression was positively correlated with SOFA respiratory system score (r _s = 0.348, p = 0.002), and SOFA liver score (r _s = 0.260, p = 0.021), but not with SOFA scores in nervous system, cardio vascular system, coagulation, and renal system (all p > 0.05)). MALT1 expression (p = 0.010), Th1 cells (p = 0.010), Th17 cells (p = 0.038), and IL‐17A (p = 0.012), except for IFN‐γ (p = 0.102), elevated in sepsis deaths compared with sepsis survivors.ConclusionPBMC MALT1 is highly expressed in sepsis patients with its overexpression associated with multiple organic dysfunctions, elevated Th17 cells, and increased mortality risk.     

Oxazolone Colitis: A Murine Model of ?T Helper Cell Type 2 Colitis Treatable with Antibodies to Interleukin 4

In this study we describe oxazolone colitis, a new form of experimental colitis. This model is induced in SJL/J mice by the rectal instillation of the haptenating agent, oxazolone, and is characterized by a rapidly developing colitis confined to the distal half of the colon; it consists of a mixed neutrophil/lymphocyte infiltration limited to the superficial layer of the mucosa which is associated with ulceration. Oxazolone colitis is a T helper cell type 2 (Th2)-mediated process since stimulated T cells from lesional tissue produce markedly increased amounts of interleukin (IL)-4 and IL-5; in addition, anti–IL-4 administration leads to a striking amelioration of disease, whereas anti–IL-12 administration either has no effect or exacerbates disease. Finally, this proinflammatory Th2 cytokine response is counterbalanced by a massive transforming growth factor-β (TGF-β) response which limits both the extent and duration of disease: lesional (distal) T cells manifest a 20–30-fold increase in TGF-β production, whereas nonlesional (proximal) T cells manifest an even greater 40–50-fold increase. In addition, anti–TGF-β administration leads to more severe inflammation which now involves the entire colon. The histologic features and distribution of oxazolone colitis have characteristics that resemble ulcerative colitis (UC) and thus sharply distinguish this model from most other models, which usually resemble Crohn''s disease. This feature of oxazolone colitis as well as its cytokine profile have important implications to the pathogenesis and treatment of UC.     

In vivo identification of glycolipid antigen-specific T cells using fluorescent CD1d tetramers

The CD1 family of major histocompatibility complex (MHC)-like molecules specializes in presenting lipid and glycolipid antigens to alpha/beta T lymphocytes, but little is known about the size of the CD1-restricted T cell population or the frequency of T lymphocytes specific for a given glycolipid antigen. Here, we report the generation and use of mouse CD1d1-glycolipid tetramers to visualize CD1d-restricted T cells. In contrast with previous BIAcore-based estimates of very short half-lives for CD1d-glycolipid complexes, we found that the dissociation rate of several different CD1d-glycolipid complexes was very slow. Fluorescent tetramers of mouse CD1d1 complexed with alpha-galactosylceramide (alphaGalCer), the antigen recognized by mouse Valpha14-Jalpha281/Vbeta8 and human Valpha24-JalphaQ/Vbeta11 natural killer T (NKT) cell T cell receptors (TCRs), allowed us for the first time to accurately describe, based on TCR specificity, the entire population of NKT cells in vivo and to identify a previously unrecognized population of NK1.1-negative "NKT" cells, which expressed a different pattern of integrins. In contrast, natural killer (NK) cells failed to bind the tetramers either empty or loaded with alphaGalCer, suggesting the absence of a CD1d-specific, antigen-nonspecific NK receptor. Mouse CD1d1-alphaGalCer tetramers also stained human NKT cells, indicating that they will be useful for probing a range of mouse and human conditions such as insulin-dependent diabetes mellitus, tumor rejection, and infectious diseases where NKT cells play an important role.     

Resting Respiratory Tract Dendritic Cells Preferentially Stimulate T Helper Cell Type 2 (Th2) Responses and Require Obligatory Cytokine Signals for Induction of ?Th1 Immunity

Consistent with their role in host defense, mature dendritic cells (DCs) from central lymphoid organs preferentially prime for T helper cell type 1 (Th1)-polarized immunity. However, the “default” T helper response at mucosal surfaces demonstrates Th2 polarity, which is reflected in the cytokine profiles of activated T cells from mucosal lymph nodes. This study on rat respiratory tract DCs (RTDCs) provides an explanation for this paradox. We demonstrate that freshly isolated RTDCs are functionally immature as defined in vitro, being surface major histocompatibility complex (MHC) II ^lo, endocytosis^hi, and mixed lymphocyte reaction^lo, and these cells produce mRNA encoding interleukin (IL)-10. After ovalbumin (OVA)-pulsing and adoptive transfer, freshly isolated RTDCs preferentially stimulated Th2-dependent OVA-specific immunoglobulin (Ig)G₁ responses, and antigen-stimulated splenocytes from recipient animals produced IL-4 in vitro. However, preculture with granulocyte/macrophage colony stimulating factor increased their in vivo IgG priming capacity by 2–3 logs, inducing production of both Th1- and Th2-dependent IgG subclasses and high levels of IFN-γ by antigen-stimulated splenocytes. Associated phenotypic changes included upregulation of surface MHC II and B7 expression and IL-12 p35 mRNA, and downregulation of endocytosis, MHC II processing– associated genes, and IL-10 mRNA expression. Full expression of IL-12 p40 required additional signals, such as tumor necrosis factor α or CD40 ligand. These results suggest that the observed Th2 polarity of the resting mucosal immune system may be an inherent property of the resident DC population, and furthermore that mobilization of Th1 immunity relies absolutely on the provision of appropriate microenvironmental costimuli.     

A defect in interleukin 12-induced activation and interferon gamma secretion of peripheral natural killer T cells in nonobese diabetic mice suggests new pathogenic mechanisms for insulin-dependent diabetes mellitus.

The function of natural killer T (NKT) cells in the immune system has yet to be determined. There is some evidence that their defect is associated with autoimmunity, but it is still unclear how they play a role in regulating the pathogenesis of T cell-mediated autoimmune diseases. It was originally proposed that NKT cells could control autoimmunity by shifting the cytokine profile of autoimmune T cells toward a protective T helper 2 cell (Th2) type. However, it is now clear that the major function of NKT cells in the immune system is not related to their interleukin (IL)-4 secretion. In fact, NKT cells mainly secrete interferon (IFN)-gamma and, activated in the presence of IL-12, acquire a strong inflammatory phenotype and cytotoxic function.     

T helper cell type 2 cytokines coordinately regulate immunoglobulin E-dependent cysteinyl leukotriene production by human cord blood-derived mast cells: profound induction of leukotriene C(4) synthase expression by interleukin 4

Human mast cells (hMCs) derived in vitro from cord blood mononuclear cells exhibit stem cell factor (SCF)-dependent comitogenic responses to T helper cell type 2 (Th2) cytokines. As cysteinyl leukotriene (cys-LT) biosynthesis is a characteristic of immunoglobulin (Ig)E-activated mucosal hMCs, we speculated that Th2 cytokines might regulate eicosanoid generation by hMCs. After passive sensitization for 5 d with IgE in the presence of SCF, anti-IgE-stimulated hMCs elaborated minimal cys-LT (0.1 +/- 0.1 ng/10(6) hMCs) and abundant prostaglandin (PG)D(2) (16.2 +/- 10.3 ng/10(6) hMCs). Priming of hMCs by interleukin (IL)-4 with SCF during passive sensitization enhanced their anti-IgE-dependent histamine exocytosis and increased their generation of both cys-LT (by 27-fold) and PGD(2) (by 2. 5-fold). Although priming with IL-3 or IL-5 alone for 5 d with SCF minimally enhanced anti-IgE-mediated cys-LT generation, these cytokines induced further six- and fourfold increases, respectively, in IgE-dependent cys-LT generation when provided with IL-4 and SCF; this occurred without changes in PGD(2) generation or histamine exocytosis relative to hMCs primed with IL-4 alone. None of these cytokines, either alone or in combination, substantially altered the levels of cytosolic phospholipase A(2) (cPLA(2)), 5-lipoxygenase (5-LO), or 5-LO activating protein (FLAP) protein expression by hMCs. In contrast, IL-4 priming dramatically induced the steady-state expression of leukotriene C(4) synthase (LTC(4)S) mRNA within 6 h, and increased the expression of LTC(4)S protein and functional activity in a dose- and time-dependent manner, with plateaus at 10 ng/ml and 5 d, respectively. Priming by either IL-3 or IL-5, with or without IL-4, supported the localization of 5-LO to the nucleus of hMCs. Thus, different Th2-derived cytokines target distinct steps in the 5-LO/LTC(4)S biosynthetic pathway (induction of LTC(4)S expression and nuclear import of 5-LO, respectively), each of which is necessary for a full integrated functional response to IgE-dependent activation, thus modulating the effector phenotype of mature hMCs.     

过敏性哮喘患者高迁移率族蛋白1、Th1/Th2细胞亚群及相关细胞因子表达分析

目的：分析高迁移率族蛋白-1（high mobility group protein-1，HMGB-1）、辅助T淋巴细胞（Th）亚群以及相关细胞因子在不同严重程度的过敏性支气管哮喘患者中的表达意义。方法：选择98例轻中重度过敏性哮喘患者和30例同期体检的健康者（对照组），采用流式细胞术分析患者以及健康者外周血CD4⁺干扰素-γ⁺（IFN-γ⁺）T细胞、CD4⁺白细胞介素-4⁺（IL-4⁺）T细胞百分比。通过酶联免疫吸附测定法（ELISA）检测血清中HMGB-1、Th1细胞因子（IFN-γ）和Th2细胞因子（IL-4、IL-5）的表达水平。采用Spearman分析HMGB-1、Th1/Th2细胞亚群及其相关细胞因子与肺功能的相关性。结果：所有哮喘患者HMGB-1、CD4⁺IL-4⁺T细胞百分比、IL-4、IL-5均高于对照组；重度组患者HMGB-1、CD4⁺IL-4⁺T细胞百分比、IL-4、IL-5高于轻、中度患者。所有患者CD4⁺IFN-γ⁺T细胞百分比、IFN-γ表达均低于对照组；重度患者CD4⁺IFN-γ⁺T细胞百分比和IFN-γ表达低于轻、中度患者。HMGB-1、IL-4水平与肺功能负相关，IFN-γ水平与肺功能正相关。结论：HMGB-1和IFN-γ、IL-4可作为评价支气管哮喘严重程度的有效指标。     

支气管哮喘气道炎症表型与Th1/Th2和IgE的相关研究

目的 分析不同气道炎症表型的支气管哮喘患者的循环血辅助性T细胞1/2(Th1/Th2)和IgE水平与临床特征的关系。方法 选择2017年6月至2018年12月于该院诊断为支气管哮喘患者共180例,根据诱导痰液中性粒细胞(Neu)和嗜酸粒细胞(Eos)百分比分为Neu组、Eos组、混合组和寡细胞组,检测循环血Th1/Th2和IgE水平,Th1细胞分泌细胞因子血清干扰素-γ(IFN-)γ和Th2细胞分泌白细胞介素-4(IL-4),比较各组患者的临床特征。结果 Eos组和混合组的Th1/Th2(0.56±0.12、0.59±0.15)明显低于Neu组(0.77±0.23)和寡细胞组(0.72±0.19),但IgE水平[(12.3±4.5)、(11.9±4.3)mg/L],比Neu组和寡细胞组[(7.6±3.2)、(7.2±3.1)mg/L]增加,IFN-γ[(32.6±9.5)、(30.5±8.6)mg/L比(21.2±6.8)、(20.9±5.7)mg/L]和IL-4[(25.7±6.8)、(23.3±6.5)mg/L比(12.4±4.3)、(11.5±4.2)mg/L]水平升高,差异有统计学意义(P<0.05)。Neu组和混合组患者哮喘病程和严重程度明显大于其他两组,吸烟和气道感染率增加;Eos组和混合组患者过敏性鼻炎和皮肤点刺试验阳性率高于其他两组,差异有统计学意义(P<0.05)。4种炎症表型组患者的肺功能包括第1秒用力呼气容积(FEV1)及与用力肺活量的比值(FEV1/FVC)、用力呼气中段流量(MMEF%)、50%用力呼气流量(FEF 50%)和75%用力呼气流量(FEF 75%)比较差异无统计学意义(P>0.05)。结论 支气管哮喘患者具有不同的炎症细胞表型,与循环血Th1/Th2和IgE水平以及临床特征有密切联系。     

Protein kinase C theta is critical for the development of in vivo T helper (Th)2 cell but not Th1 cell responses

The serine/threonine-specific protein kinase C (PKC)-theta is predominantly expressed in T cells and localizes to the center of the immunological synapse upon T cell receptor (TCR) and CD28 signaling. T cells deficient in PKC-theta exhibit reduced interleukin (IL)-2 production and proliferative responses in vitro, however, its significance in vivo remains unclear. We found that pkc-theta(-/-) mice were protected from pulmonary allergic hypersensitivity responses such as airway hyperresponsiveness, eosinophilia, and immunoglobulin E production to inhaled allergen. Furthermore, T helper (Th)2 cell immune responses against Nippostrongylus brasiliensis were severely impaired in pkc-theta(-/-) mice. In striking contrast, pkc-theta(-/-) mice on both the C57BL/6 background and the normally susceptible BALB/c background mounted protective Th1 immune responses and were resistant against infection with Leishmania major. Using in vitro TCR transgenic T cell-dendritic cell coculture systems and antigen concentration-dependent Th polarization, PKC-theta-deficient T cells were found to differentiate into Th1 cells after activation with high concentrations of specific peptide, but to have compromised Th2 development at low antigen concentration. The addition of IL-2 partially reconstituted Th2 development in pkc-theta(-/-) T cells, consistent with an important role for this cytokine in Th2 polarization. Taken together, our results reveal a central role for PKC-theta signaling during Th2 responses.