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PubMed1996

The role of Th2 type CD4+ T cells and Th2 type CD8+ T cells in asthma.

The cellular inflammatory responses which are seen in allergic and asthmatic diseases are viewed as being quite strongly dependent on the activities of T cells and their products. The major T cell subset involved appears to be the so-called CD4+ Th2 subset which produces interleukin-4 (IL-4) and interleukin-5 (IL-5). In vitro and in vivo experiments have indicated that IL-4 is a key regulator in these kinds of immune responses, not only switching B cells to IgE production, but acting on CD4+ T cells to drive their development towards a Th2 phenotype. Recent results have shown that the functional phenotype of CD8+ T cells can be switched from interferon gamma production to IL-4 and IL-5 production by the presence of IL-4. This could prove an especially important phenomenon since it is the production of interferon gamma by CD8 T cells which is seen as necessary for protection against virus infection. This short review updates our current knowledge of how IL-4 can act on CD4+ and CD8+ T cell subsets in in vivo models of asthma and allergic disease.

Animals↗
PubMed1998

Immunotherapy suppresses both Th1 and Th2 responses by allergen stimulation, but suppression of the Th2 response is a more important mechanism related to the clinical efficacy of immunotherapy for perennial allergic rhinitis.

Increased attention has recently been directed at the possibility that the clinical efficacy of immunotherapy might be elaborated by alteration of T-cell reactivity. However, there is no general agreement among different investigators regarding the effect of immunotherapy on Th-cell reactivity. Peripheral blood mononuclear cells (PBMCs) from 15 nonatopic subjects and 76 patients with perennial allergic rhinitis (18 untreated patients and 58 patients on immunotherapy) were cultured in the absence and in the presence of a major Dermatophagoides farinae allergen, Der f 1, and the levels of IgE, interleukin-5 (IL-5), interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) in the culture supernatants were determined. The difference between the absence and presence of Der f 1 was calculated to consider the Der f 1-dependent synthesis of IgE, IL-5, IFN-gamma and TNF-alpha. The levels of Der f 1-dependent synthesis of IgE, IL-5 and TNF-alpha were significantly higher in the untreated group than in the nonatopic group, whereas Der f 1-dependent synthesis of IFN-gamma was significantly lower in the untreated group than in the nonatopic group. Immunotherapy decreased the enhanced Der f 1-dependent synthesis of IgE, IL-5 and TNF-alpha, and further decreased the suppressed Der f 1-dependent synthesis of IFN-gamma as the therapy proceeded. The levels of Der f 1-dependent synthesis of IgE and IL-5 did not differ between nonatopic individuals and patients whose duration of immunotherapy was 10 or more years. The levels of Der f 1-dependent synthesis of IgE and IL-5, but not of IFN-gamma and TNF-alpha, were correlated significantly with the levels of symptom scores. In addition, the levels of Der f 1-dependent synthesis of IgE and IL-5, but not of IFN-gamma and TNF-alpha, differed significantly between good and poor responders. In conclusion, immunotherapy for perennial allergic rhinitis may possibly work via induction of tolerance or anergy of both Th1- and Th2 cells. However, our study is likely to support a view that the mechanisms responsible for the clinically beneficial effects of immunotherapy principally involve the tolerance of Th2- rather than Th1 cells. In addition, suppression of IgE synthesis is also likely to be linked to the clinical efficacy of immunotherapy for perennial allergic rhinitis.

Allergens↗
PubMed2005

CD8 alpha+, but not CD8 alpha-, dendritic cells tolerize Th2 responses via contact-dependent and -independent mechanisms, and reverse airway hyperresponsiveness, Th2, and eosinophil responses in a mouse model of asthma.

Splenic CD8alpha+ dendritic cells reportedly tolerize T cell responses by inducing Fas ligand-mediated apoptosis, suppressing IL-2 expression, or catabolizing T cell tryptophan reserves through expression of IDO. We report in this study that CD8alpha+, but not CD8alpha-, dendritic cells purified from the spleens of normal mice can tolerize the Th2 responses of cells from asthma phenotype mice through more than one mechanism. This tolerance could largely be reversed in vitro by anti-IL-10 or anti-TGFbeta Ab treatment. However, loss of direct dendritic cell-T cell contact also reduced tolerance, although to a lesser extent, as did adding the IDO inhibitor 1-methyltryptophan or an excess of free tryptophan to the cultures. Within 3 wk of reconstituting asthma phenotype mice with 1 x 10(5) OVA-pulsed CD8alpha+, but not CD8alpha-, dendritic cells, the mice experienced a reversal of airway hyperresponsiveness, eosinophilic airway responses, and pulmonary Th2 cytokine expression. This data indicates that CD8alpha+ dendritic cells can simultaneously use multiple mechanisms for tolerization of T cells and that, in vivo, they are capable of tolerizing a well-established disease complex such as allergic lung disease/asthma.

Allergens↗
PubMed1997

[An imbalance between Th1 and Th2-like cytokines in patients with autoimmune diseases--differential diagnosis between Th1 dominant autoimmune diseases and Th2 dominant autoimmune diseases].

An imbalance between T helper cell (Th)1 and Th2-like cytokines has been described in several autoimmune diseases. Organ specific autoimmune diseases such as multiple sclerosis (MS) and inflammatory bowel diseases (IBD) are caused by Th1 dominant immune responses. On the contrary, systemic autoimmune diseases such as systemic lupus erythematosus (SLE) and Sjögren's syndrome(SS) are characterized by Th2 dominant imbalance of cytokine production. It might be useful for differential diagnosis among patients with various autoimmune diseases such as SLE, SS, IBD, and MS to measure the serum levels of cytokines such as IL-10, IFN gamma, and TNF alpha using ultrasensitive enzyme-linked immunosorbent assay system.

Animals↗
PubMed1999

CpG oligodeoxynucleotides can circumvent the Th2 polarization of neonatal responses to vaccines but may fail to fully redirect Th2 responses established by neonatal priming.

Neonatal murine responses to a panel of conventional vaccines differ qualitatively from adult responses by a particular polarization toward a Th2 pattern and a frequent limitation of the Th1 and CTL responses required for protection against intracellular microorganisms. In contrast, DNA vaccines induce adult-like Th1/CTL neonatal responses against the same vaccine Ags. In this report, we show that this can be related to their content in unmethylated CpG motifs. Oligodeoxynucleotides (ODN) containing CpG motifs activate neonatal APCs to produce IL-12 in vitro and induce adult-like Th1 responses to tetanus toxoid and measles Ags in vivo, with production of IgG2a-specific Abs and adult-like secretion of IFN-gamma and IL-5 by Ag-specific T cells. However, in spite of their capacity to trigger neonatal B cell proliferation in vitro, CpG-ODN only partially enhanced early life Ab responses. Finally, using Th1-driving CpG-ODN with the boosting dose of a protein vaccine was sufficient to redirect adult but not neonatally primed Th2 responses. These observations could be important for the development of novel vaccines that will have to be effective early in life.

Animals↗
PubMed2001

Th2 polarization of the immune response of BALB/c mice to Ixodes ricinus instars, importance of several antigens in activation of specific Th2 subpopulations.

BALB/c mice were infested with Ixodes ricinus larvae, nymphs or adults. Expression of IL-4 and IFN-gamma mRNA in axillary and brachial draining lymph node cells were measured by competitive quantitative reverse transcription-polymerase chain reaction 9 days after the beginning of primary-infestation. IL-4 mRNA was always higher than that of IFN-gamma mRNA for all tick instars. Moreover, IL-4 mRNA expression progressively increased during nymphal primary-infestation with a high burst of expression 7 days after the beginning of infestation. No evolution of IFN-gamma mRNA expression was detected. Draining lymph node cells of infested BALB/c produced higher level of IL-4 than IFN-gamma following in vitro restimulation with adult tick saliva, salivary gland extract (SGE) or with five selected different chromatographic fractions of SGE. Anti-tick IgG1 antibodies but no IgG2a were detected in BALB/c pluri-infested with I. ricinus nymphs, which confirmed the Th2 polarization of the immune response.

Animals↗
PubMed2004

Hypersensitive site 7 of the TH2 locus control region is essential for expressing TH2 cytokine genes and for long-range intrachromosomal interactions.

Several regulatory regions are important for the expression of genes encoding T helper type 2 (T(H)2) cytokines, including T(H)2-specific DNase I hypersensitivity sites in the T(H)2 cytokine locus control region. Among these sites, Rad50 hypersensitive site 7 (RHS7) shows rapid T(H)2-specific demethylation after antigenic stimulation. To investigate the function of RHS7 in T(H)2 cell differentiation, we have generated RHS7-deficient mice. CD4(+) T cells and mast cells showed a notable reduction in T(H)2 cytokine expression in vitro and T(H)2 responses in vivo were considerably impaired in RHS7-deficient mice. Deletion of RHS7 did not affect the expression of a linked Rad50 gene, but it did reduce long-range intrachromosomal interactions between the locus control region and promoters of the T(H)2 cytokine genes. Our findings show that RHS7 is essential for the proper regulation of T(H)2 cytokine gene expression.

ATP-Binding Cassette Transporters↗
PubMed2005

Increased Th1 and Th2 immune reactivity with relative Th2 dominance in patients with acute exacerbation of schizophrenia.

AIM: To determine concentration of T helper (Th(1)) cytokines and Th(2) cytokines in patients with acute exacerbation of schizophrenia and compare the cytokine profiles between subtypes of schizophrenia. METHOD: One hundred inpatients with acute exacerbation of schizophrenia and 34 matched healthy subjects from the same population without psychiatric history were included in the study. According to predominant symptom complexes the patients were divided into three subgroups: hallucinations and delusions (n=36); disorganized behavior (n=33), and primary, enduring negative or deficit symptoms (n=31). In vitro IFN-gamma and IL-4 secretion by peripheral blood mononuclear cells after stimulation with ionomycin and phorbol 12 myristate 13 acetate was measured by enzyme-linked immunosorbent assay (ELISA) tests. RESULTS: Significant increase in in vitro secretion of IFN-gamma (21,505 vs 14,915 pg/mL; P=0.037; independent samples t test) and IL-4 (32 vs 15 pg/mL; P<0.001) with a shift to the Th(2) (1,022 vs 1,432 pg/mL; P=0.005) immune response was observed in patients with schizophrenia compared to healthy controls. We found pronounced effects of age and age at first hospitalisation on the Th(1)/Th(2) immune balance (R(2)=0.068; P=0.037). There were no significant differences in in vitro secretion of IFN-gamma (P=0.734; one-way analysis of variance), IL-4 (P=0.485) and IFN-gamma/IL-4 ratio (P=0.293) between the subgroups of patients with schizophrenia. CONCLUSION: Our findings indicate a simultaneous increase of in vitro reactivity of both Th(1) and Th(2) arm of cell mediated immunity, with a relative predominance of Th(2) immunity in patients with acute exacerbation of schizophrenia.

Acute Disease↗
PubMed1994

Different growth factor requirements for human Th2 cells may reflect in vivo induced anergy.

We previously reported the isolation of allergen-specific Th2 lines and clones from atopy patch test (APT) sites of atopic dermatitis (AD) patients. Upon stimulation with allergen or anti-CD3+ phorbol myristate acetate (PMA) IL-4 was released with or without IL-5, while no (or extremely low concentrations of) IL-2 and interferon-gamma (IFN-gamma) were detectable. A high IL-4/IFN-gamma ratio facilitates production of allergen-specific IgE, of which high levels are observed in AD patients. Here we show that the above mentioned Th2 cells are notably different from murine Th2 cells. Not IL-4, which is the autocrine acting growth factor for murine Th2 cells, but IL-2 was needed for proliferation of these human APT-derived Th2 lines and clones. Of significance, unless exogenous IL-2 was added, no proliferative response to allergen, presented by Epstein-Barr virus-transformed B (EBV-B) cells, non-T cells or IgE-bearing Langerhans cells (LC), occurred. Lack of proliferation and IL-2 production after full T cell receptor (TCR) triggering is a characteristic first described for in vitro anergized T cells. However, like the clones we describe in this study, anergic T cells may retain production of cytokines other than IL-2. A further resemblance between anergic T cells and the human Th2 clones reported here is that IL-4 can enhance IL-2-driven proliferation, but is not capable of inducing T cell growth by itself. The absence of IL-4-driven proliferation differentiates human Th2 cells from murine Th2 cells. Both produce IL-4 when stimulated in a cognate fashion, but only murine Th2 cells will proliferate. We conclude that the presently reported human Th2 cells are different from murine Th2 cells, in that they need other T cells to produce IL-2 required for their expansion. Moreover, the Th2 cells phenotypically resemble anergic T cells. As yet, however, we have no clue as to whether these features account for the current Th2 cells only or for human Th2 cells in general. We hypothesize that the Th2 phenotype of AD skin-derived, allergen-specific T cells may be induced in vivo by LC, which lack CD80, and therefore do not provide secondary signals through CD28-CD80 interaction.

Adult↗
PubMed2002

IgE cross-linking or lipopolysaccharide treatment induces recruitment of Th2 cells to the lung in the absence of specific antigen.

We previously showed that Th1 cells can increase recruitment of Th2 cells to the lungs even in the absence of the Th2-specific Ag. The fact that Th2 recruitment is independent from the Th2 cell Ag suggested that Th1 cells may support Th2 cell recruitment using their Ag-nonspecific proinflammatory functions. To investigate the potential for inflammatory stimuli that are distinct from Ag-specific signals to affect the recruitment of T cells, we tested whether cross-linking of IgE or treatment with LPS modulated influx of Th2 cells into the airways in the presence or absence of inhaled Ag. When naive mice that had been treated with OVA-specific Th2 cells and passively sensitized with anti-DNP IgE were challenged by intranasal administration of either DNP-haptenated OVA or DNP-BSA, increased numbers of Th2 cells were recruited to the lung compared with mice challenged intranasally with OVA alone. Intranasal administration of LPS also increased recruitment of Th2 cells to the airways. These two distinct inflammatory stimuli increased the numbers of recruited Th2 cells equally with or without concurrent challenge using the cognate Th2 Ag. This Ag-independent recruitment of Th2 cells to the lung was not associated with localization of these cells to the regional lymph nodes and was independent of Th2 cell activation. Interestingly, P- or E-selectin contributed to Th2 cell recruitment to the lung. These data suggest that Th2 cells of the adaptive immune response are similar to cells of the innate immune response in their lack of requirement for protein Ag to initiate cell recruitment. They demonstrate further that recruitment can occur independently of Ag-dependent activation.

Adjuvants, Immunologic↗
PubMed2006

Chromatin remodeling at the Th2 cytokine gene loci in human type 2 helper T cells.

The differentiation of mouse naïve CD4 T cells into type 2 helper (Th2) cells is accompanied by chromatin remodeling at the nucleosomes associated with the IL-4, IL-13 and IL-5 genes. However, little is known about how chromatin remodeling of these Th2 cytokine gene loci occurs in human Th2 cells. We herein established an in vitro culture system in which both Th1 and Th2 cells are efficiently differentiated from human peripheral blood naïve CD4 T cells. This system allowed us to investigate the chromatin status at the Th2 cytokine gene loci and the IFNgamma locus in human Th2 and Th1 cells, respectively. In typical individuals, the chromatin remodeling indicated by the induction of hyper-acetylation of histone H3 lysine 9 and hyper-methylation of histone H3 lysine 4 was induced at the whole Th2 cytokine gene loci in developing Th2 cells. We more precisely assessed the methylation status of histone H3 lysine 4 at the Th2 cytokine gene loci (IL-5 exon 3, IL-5 promoter, IL-5/RAD50 intergenic region, RAD50 promoter, CGRE, CNS1, IL-13 promoter, IL-4 promoter, and VA enhancer regions) and the IFNgamma locus in developing Th1 and Th2 cells prepared from 20 healthy volunteers. Th2-cell specific chromatin remodeling was induced at most of the Th2 cytokine gene loci. In parallel with the induction of chromatin remodeling, GATA3 mRNA was preferentially expressed in developing Th2 cells, whereas T-bet, HLX and ROG mRNA was selectively expressed in developing Th1 cells.

Acetylation↗
PubMed2000

A pathogenic role of Th2 responses on the severity of encephalomyelitis induced in mice by herpes simplex virus type 2 infection.

A pathogenic role of Th2 cells and their cytokine products (IL-4 and IL-10, Th2 cytokines) on the development of herpes simplex myelitis (HSM) was studied in mice exposed to footpad injection of herpes simplex virus type 2 (HSV-2). Morbidity and mortality of mice with HSM (HSM mice) increased when they were treated with a mixture of Th2 cytokines. Additionally, survival rates of HSM mice increased when they were treated with a mixture of mAbs for Th2 cytokines. As compared with HSM mice treated with saline, the growth of HSV-2 in spinal cords of HSM mice treated with the mixture of Th2 cytokines increased. Th2 cells (myelitis-associated Th2 cells, MTh2 cells) were demonstrated among cerebrospinal fluid cells from HSM mice. After the stimulation with HSV-2 antigen (Ag), MTh2 cells from HSM mice previously treated with the mixture of Th2 cytokines produced enhanced amounts of Th2 cytokines into their culture fluids, as compared with the amount of Th2 cytokines produced by MTh2 cells. Th2 cells were also demonstrated in mononuclear cells from spleens of HSM mice. When compared with HSM mice inoculated with splenic CD4(+) T cells from normal mice, morbidity and mortality of HSM mice inoculated with MTh2 cells markedly increased. These results indicated that the severity of HSM induced in mice by footpad injection of HSV-2 was influenced by MTh2 cells or Th2 cytokines released from these MTh2 cells. Th2 responses manifested in mice by HSV-2 infection may act as a pathogenic enhancer of HSM severities.

Adoptive Transfer↗
PubMed2005

Exploiting worm and allergy models to understand Th2 cytokine biology.

PURPOSE OF REVIEW: Helminthic parasites and many allergens trigger highly polarized Th2-type immune responses. In most helminth infections, the Th2 response often leads to parasite expulsion or sequestration. During murine Schistosoma mansoni infection, however, the parasites persist and the chronic Th2 response induces severe pathological changes in the gut and liver. Thus, the study of schistosome infections in mice has become a popular model to study the pathogenesis of Th2 cytokine-mediated disease. This review will discuss recent findings from the schistosomiasis model that may be relevant to the understanding of allergic inflammation, asthma and Th2 cytokine biology in general. RECENT FINDINGS: Evidence is accumulating that the Th2 pathway is not a 'default pathway' but one that is actively instructed by mechanisms that are only beginning to be understood. Other areas of intensive investigation include studies on alternatively activated macrophages, the role of dendritic cells in Th2 response development, the inhibitory function of IL-10, regulatory T-cells and decoy receptors on chronic Th2-mediated inflammation, and the role of chitinases in mediating Th2 disease. Finally, the development of novel eosinophil-deficient mice has also accelerated our understanding of the contribution of this important cell type to Th2 immunity. SUMMARY: Many findings from the schistosomiasis model have been subsequently demonstrated in models of allergic disease, illustrating the utility of this model to dissect basic mechanisms of Th2-mediated inflammation. Further study of helminth-induced Th2 responses may expedite the discovery of new therapeutics for a wide range of Th2-associated diseases.

Animals↗
PubMed2002

Antigen-nonspecific recruitment of Th2 cells to the lung as a mechanism for viral infection-induced allergic asthma.

Respiratory viral infections have been shown to trigger exacerbations of asthma; however, the mechanism by which viral Th1-type inflammation exacerbates an allergic Th2-type disease remains unclear. We have previously shown that although adoptively transferred Th2 cells are inefficiently recruited to the lung in response to Ag, cotransfer of Th1 cells can increase accumulation of Th2 cells. In this study, we show that respiratory viral infection increases recruitment of resting Th2 cells specific for OVA even in the absence of OVA challenge. These findings suggest that the mechanism by which Th1-type inflammation enhances allergy is via an effect on recruitment. To study the role of the antigenic specificity of Th1 cells in the enhancement of Th2 cell recruitment and to determine whether virus-induced recruitment of OVA-specific Th2 cells may involve Th1 cells specific to a different Ag, we tested whether hen egg lysozyme-specific Th1 cells could synergize with OVA-specific Th2 cells. Challenge of mice that had received adoptively transferred Th1 cells plus Th2 cells induced the expression of inflammatory chemokines in the lung and increased both recruitment and activation of Th2 cells, leading to eosinophil recruitment, even in the absence of challenge with the Th2 Ag. Interestingly, as IL-5 supports eosinophilia, culture of resting Th2 cells with fresh APC induced production of IL-5 in the absence of specific Ag. Thus, Ag-specific activation of Th1 cells enhances the recruitment potential of the lung leading to recruitment and activation of Th2 cells. This implies that circulating Th2 cells in allergic individuals could enter the lungs in response to infection or inflammation and become activated to trigger allergy.

Animals↗
PubMed2001

Resistance of activated human Th2 cells to NO-induced apoptosis is mediated by gamma-glutamyltranspeptidase.

Activation-induced death of inflammatory cells (AICD) has an important function in immune maintenance. Type 1 Th cells are known to be more susceptible to AICD than Th2 cells. In the current study we examined whether NO-induced apoptosis also preferentially eliminates Th1 cells over Th2 cells. Naive human Th lymphocytes (CD4(+)CD45RO(-)) were activated in vitro for 1 week in the presence of IL-12 plus anti-IL-4 or IL-4 plus anti-IL-12 to generate Th1- and Th2-polarized cultures respectively. Cultures were exposed to the NO donors Spermine-nonoate (Sper) and DPTA-nonoate to study NO-induced apoptosis. We found that NO preferentially induced apoptosis in Th1-polarized cells as demonstrated by Annexin staining in the presence of 10 microM Sper (70 +/- 16 versus 23 +/- 4.4% in Th2 cells P: < 0.01) and by DioC6 staining (38 +/- 10 versus 11 +/- 5% in Th2 cells, P: < 0.01). The mechanism of NO-induced apoptosis in Th1/Th2-polarized cells was distinct from AICD and Fas-induced apoptosis. Differential sensitivity between Th1- and Th2-polarized cultures originated at the level of intracellular glutathione (GSH) metabolism. GSH levels were higher in Th2 cells (1.6 +/- 0.2-fold Th1, P: < 0.01). High intracellular GSH in Th2-polarized cells did not account for reduced susceptibility to NO per se, since the inhibition of gamma-glutamyltrans-peptidase (gamma-GT), which is involved in GSH import, sensitized Th2 cells to NO-induced apoptosis without GSH depletion. Therefore, higher activity of gamma-GT in Th2 cells (2.1 +/- 0.4-fold Th1, P: < 0.001) specifically protects Th2 cells against NO-induced apoptosis. Preferential NO-induced elimination of human Th1 cells at sites of inflammation may thus select Th2 cells and contribute to immune deviation.

Apoptosis↗
PubMed2002

A Chlamydia trachomatis-specific Th2 clone does not provide protection against a genital infection and displays reduced trafficking to the infected genital mucosa.

A T helper type 1 (Th1) response is essential for resolving genital infections with the mouse pneumonitis biovar of Chlamydia trachomatis (MoPn). However, T-cell-dependent anti-chlamydial antibody is produced and may also contribute to protective immunity. We produced a MoPn-specific CD4 Th2 clone (Th2-MoPn) to study the role of a Th2 response during infection. We found that Th2-MoPn was unable to eradicate chlamydiae from the genital tract (GT) when it was transferred into MoPn-infected nude mice. Mice that received Th2-MoPn produced greater titers of MoPn-specific serum immunoglobulin G (IgG) antibody than mice that received a MoPn-specific Th1 clone (Th1-MoPn) (log(10) titers, 1.89 +/- 0.84 and 0.58 +/- 0.76 [mean +/- standard deviation], respectively [P < 0.01]). Also, the IgG isotypes were different for the two groups; whereas IgG1 was associated with Th2-MoPn, IgG2a was associated with Th1-MoPn. Also, infected nude mice that received Th2-MoPn produced higher levels of IgA in vaginal secretions. Although clone Th2-MoPn was detected in the GT, it was less efficient at migrating (112 +/- 35.6 labeled Th2 clone cells/10(5) GT cells) than Th1-MoPn (505 +/- 51.6 Th1 clone cells/10(5) GT cells) (P < 0.001, as determined by a t test). This may have been due to reduced expression of alpha4beta7 and P-selectin ligand 1 on Th2-MoPn. However, Th2-MoPn cells were retained in the GT during chronic infection and comprised 10 to 15% of the total GT cells 80 days after transfer. The data show that the MoPn-specific Th2 cells are important for serum and vaginal antibody production and may accumulate in the GT during chronic infection.

Adoptive Transfer↗
PubMed2002

Early events of TCR signaling are distinct in human Th1 and Th2 cells.

To study the requirements for activation of human Th1 and Th2 cells, soluble peptide/DR1 complexes were prepared from naturally expressed DR1 protein. When immobilized, this material induced T cell activation, as revealed by CD25 up-regulation. Unexpectedly, Th2 cells required a higher density of peptide/DR1 complexes than Th1 cells to initiate CD25 up-regulation. Similar findings were obtained with immobilized or soluble and cross-linked anti-CD3 mAb. In contrast, peptide/DR1 complexes displayed on the surface of nonprofessional APC similarly induced CD25 up-regulation in Th1 and Th2 cells. Signaling events distinguishing human Th1 and Th2 cells following TCR engagement by anti-CD3 mAb were then studied. It was observed that upon TCR triggering, the overall tyrosine phosphorylation profiles were fainter in Th2 than in Th1 clones. Similar results were obtained with Th1- and Th2-polarized polyclonal lines. Varying the dose of anti-CD3 mAb, the kinetics of activation, and coengagement of CD3 and CD28 failed to increase tyrosine phosphorylation in Th2 cells to levels reached in Th1 cells. In contrast, treatment with the tyrosine phosphatase inhibitor phenylarsine oxide resulted in similar tyrosine phosphorylation levels in Th2 and Th1 cells. These findings indicated that Th2 cells had an intrinsically lower TCR-induced tyrosine phosphorylation capacity than Th1 cells, which might be controlled by Th1- and Th2-specific phosphatase profiles. Finally, a weaker association was found between ZAP-70 and CD3zeta in Th2 than in Th1 cells after TCR engagement. Taken together, these results constituted evidence that early events in the TCR signaling cascades are distinct in human Th1 and Th2 cells.

Antibodies, Monoclonal↗
PubMed2004

CD4+CD25+ T cells regulate airway eosinophilic inflammation by modulating the Th2 cell phenotype.

We used a TCR-transgenic mouse to investigate whether Th2-mediated airway inflammation is influenced by Ag-specific CD4+CD25+ regulatory T cells. CD4+CD25+ T cells from DO11.10 mice expressed the transgenic TCR and mediated regulatory activity. Unexpectedly, depletion of CD4+CD25+ T cells before Th2 differentiation markedly reduced the expression of IL-4, IL-5, and IL-13 mRNA and protein when compared with unfractionated (total) CD4+ Th2 cells. The CD4+CD25--derived Th2 cells also expressed decreased levels of IL-10 but were clearly Th2 polarized since they did not produce any IFN-gamma. Paradoxically, adoptive transfer of CD4+CD25--derived Th2 cells into BALB/c mice induced an elevated airway eosinophilic inflammation in response to OVA inhalation compared with recipients of total CD4+ Th2 cells. The pronounced eosinophilia was associated with reduced levels of IL-10 and increased amounts of eotaxin in the bronchoalveolar lavage fluid. This Th2 phenotype characterized by reduced Th2 cytokine expression appeared to remain stable in vivo, even after repeated exposure of the animals to OVA aerosols. Our results demonstrate that the immunoregulatory properties of CD4+CD25+ T cells do extend to Th2 responses. Specifically, CD4+CD25+ T cells play a key role in modulating Th2-mediated pulmonary inflammation by suppressing the development of a Th2 phenotype that is highly effective in vivo at promoting airway eosinophilia. Conceivably, this is partly a consequence of regulatory T cells facilitating the production of IL-10.

Administration, Inhalation↗