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PubMed2001

IL-12-induced reversal of human Th2 cells is accompanied by full restoration of IL-12 responsiveness and loss of GATA-3 expression.

IL-12 is a potent inducer of IFN-gamma production and drives the development of Th1 cells. Human polarized Th2 cells do not express the signaling beta2-subunit of the IL-12R and, therefore, do not signal in response to IL-12. The question was raised as to what extent the loss of the IL-12Rbeta2 chain in Th2 cells has bearing on the stability of the human Th2 phenotype. In the present report, we show that restimulation of human fully polarized Th2 cells in the presence of IL-12 primes for a shift towards Th0/Th1 phenotypes, accompanied by suppression of GATA-3 expression and induction of T-bet expression. These reversed cells are further characterized by a marked IL-12Rbeta2 chain expression and fully restored IL-12-inducible STAT4 activation. The IL-12-induced phenotypic shift proved to be stable as a subsequent restimulation in the presence of IL-4 and in the absence of IL-12 could not undo the accomplished changes. Identical results were obtained with cells from atopic patients, both with polyclonal Th2 cell lines and allergen-specific Th2 cell clones. These findings suggest the possibility of restoring IL-12 responsiveness in established Th2 cells of atopic patients by stimulation in the presence of IL-12, and that IL-12-promoting immunotherapy can be beneficial for Th2-mediated immune disorders, targeting both naive and memory effector T cells.

Allergens↗
PubMed2004

Probabilistic regulation of IL-4 production in Th2 cells: accessibility at the Il4 locus.

IL-4 secreting and nonsecreting cells from Th2 cultures have a similar probability of producing IL-4 upon subsequent stimulation, implying that there is stochastic element in IL-4 production by stimulated Th2 cells. Purified IL-4 producers and nonproducers have similar Gata3 and c-maf mRNA expression. Il4 gene accessibility, analyzed by restriction enzyme accessibility (REA) at sites in the promoter, in the second intron (DNase I hypersensitivity sites HSII and HSIII) and in CNS-1 in the two populations was also similar. However, upon TCR stimulation, site VA, which is 5 kB 3' of exon 4, displayed a striking increase in accessibility but REA was 2- to 3-fold greater in producers than nonproducers. Cyclosporin A treatment inhibited VA opening, implying the involvement of NFAT in increased VA accessibility. Induction of VA accessibility is sensitive to cycloheximide, suggesting an additional factor(s) is needed. Thus, opening of VA is a probabilistic event determining which Th2 cells transcribe Il4.

Animals↗
PubMed2001

1alpha,25-Dihydroxyvitamin d3 has a direct effect on naive CD4(+) T cells to enhance the development of Th2 cells.

1alpha,25-Dihydroxyvitamin D3 (vitD3) is an immunoregulatory hormone with beneficial effects on Th1 mediated autoimmune diseases. Although the inhibitory effects of vitD3 on macrophages and dendritic cells are well documented, any direct effects of vitD3 on Th cell development are not clearly defined. Using CD4(+)Mel14(+) T cells derived from mice on a BALB/c and a C57BL/6 genetic background we examined the effect of vitD3 on Th cell development. We demonstrated that vitD3 affects Th cell polarization by inhibiting Th1 (IFN-gamma production) and augmenting Th2 cell development (IL-4, IL-5, and IL-10 production). These effects were observed in cultures driven with splenic APC and Ag, as well as with anti-CD3 and anti-CD28 alone, indicating that CD4(+) cells can also be direct targets for vitD3. The enhanced Th2 development by vitD3 was found in both BALB/c and C57BL/6 mice. An increased expression of the Th2-specific transcription factors GATA-3 and c-maf correlated with the increased production of Th2 cytokines after vitD3 treatment. The vitD3-induced effects were largely mediated via IL-4, because neutralization of IL-4 almost completely abrogated the augmented Th2 cell development after vitD3 treatment. These findings suggest that vitD3 acts directly on Th cells and can, in the absence of APC, enhance the development of a Th2 phenotype and augment the expression of the transcription factors c-maf and GATA-3. Our findings suggest that the beneficial effects of vitD3 in autoimmune diseases and transplantation operate through prevention of strong Th1 responses via the action on the APC, while simultaneously directly acting on the T cell to enhance Th2 cell development.

Animals↗
PubMed1998

[Cytokine measurement at a single-cell level to analyze human Th1 and Th2 cells].

Th1 cells, which produce IL-2 and IFN gamma, are responsible for cell-mediated immune responses, and Th2 cells, which produce IL-4 and IL-5, facilitate humoral immune responses. It has been shown that these two types of cells play critical roles in defensive immune responses and in immunopathological disorders such as allergic reactions and autoimmune diseases, and the methods of detecting Th1 and Th2 cells have become more important. A newly developed technique enables intracellular cytokines to be stained and detected on flow cytometry at a single-cell level. To show the existence of human Th1/Th2 cells, naive human CD4+ T cells were differentiated into Th cells in vitro, and Th1/Th2 cells were clearly demonstrated using intracellular IL-4 and IFN gamma staining. IL-4 promoted Th2 differentiation and IL-12 did Th1, as previously reported. Th1 and Th2 cells among human peripheral blood T cell population also can be detected by this technique using double staining for IL-4 and IFN gamma, and the predominance of Th1 cells among peripheral blood T cells were suggested. Measurement of intracellular cytokines is a useful technique, and will be used in the field of clinical laboratory medicine to further clarify the pathophysiology of immunological disorders.

CD4-Positive T-Lymphocytes↗
PubMed1998

Crossregulation between Th1 and Th2 cells.

Th1 and Th2 subsets have been characterized on the basis of the cytokines they secrete and the immune functions they mediate. Th1 cells secrete IL-2, IFN-gamma, and lymphotoxin and are important in the cell-mediated response; Th2 cells secrete IL-4, IL-5, IL-10, and IL-13 and are important in the control of macrophage function and in the stimulation of particular immunoglobulin isotypes. Cytokines secreted by Th1 and Th2 cells regulate the growth and differentiation of Th1 and Th2 cells in both positive and negative ways; this has been termed crossregulation. Much work has concentrated on the factors important in the differentiation of these Th subsets, and it has been established that Th cells become committed to a Th1 or Th2 phenotype within 48 hrs of antigenic stimulation. During the differentiation process irreversible changes in the expression and function of cytokine receptors occur that provide an explanation for the observed crossregulatory features of Th1 and Th2 cells. In this review we summarize the crossregulation between Th1 and Th2 cells in terms of the changes in cytokine receptor expression and function that occur during differentiation.

Animals↗
PubMed2006

STAT1 in peripheral tissue differentially regulates homing of antigen-specific Th1 and Th2 cells.

Th1 and Th2 effector CD4+ T cells orchestrate distinct counterregulatory biological responses. To deliver effective tissue Th1- and Th2-type responses, Th1 and Th2 cell recruitment into tissue must be differentially regulated. We show that tissue-derived STAT1 controls the trafficking of adoptively transferred, Ag-specific, wild-type Th1 cells into the lung. Trafficking of Th1 and Th2 cells is differentially regulated as STAT6, which regulates Th2 cell trafficking, had no effect on the trafficking of Th1 cells and STAT1 deficiency did not alter Th2 cell trafficking. We demonstrate that STAT1 control of Th1 cell trafficking is not mediated through T-bet. STAT1 controls the recruitment of Th1 cells through the induction of CXCL9, CXCL10, CXCL11, and CXCL16, whose expression levels in the lung were markedly decreased in STAT1-/- mice. CXCL10 replacement partially restored Th1 cell trafficking in STAT1-deficient mice in vivo, and deficiency in CXCR3, the receptor for CXCL9, CXCL10, and CXCL11, impaired the trafficking of adoptively transferred Th1 cells in wild-type mice. Our work identifies that STAT1 in peripheral tissue regulates the homing of Ag-specific Th1 cells through the induction of a distinct subset of chemokines and establishes that Th1 and Th2 cell trafficking is differentially controlled in vivo by STAT1 and STAT6, respectively.

Adoptive Transfer↗
PubMed2003

CD4+CD25+ regulatory T cells suppress differentiation and functions of Th1 and Th2 cells, Leishmania major infection, and colitis in mice.

Regulatory T cells play a major role in modulating the immune response. However, most information on these cells centers on autoimmunity, and there is also considerable controversy on the functional characteristics of these cells. Here we provide direct in vitro and in vivo evidence that CD4+CD25+ regulatory T cells inhibit the differentiation and functions of both Th1 and Th2 cells. Importantly, CD4+CD25+ T cells suppressed the disease development of Leishmania major infection in SCID mice reconstituted with naive CD4+CD25- T cells. Furthermore, CD4+CD25+ T cells inhibited the development of colitis induced by both Th1 and Th2 cells in SCID mice. Our results therefore document that CD4+CD25+ regulatory T cells suppress both Th1 and Th2 cells and that these regulatory T cells have a profound therapeutic potential against diseases induced by both Th1 and Th2 cells in vivo.

Adoptive Transfer↗
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↗
PubMed2005

Cutting edge: the development of IL-4-producing B cells (B effector 2 cells) is controlled by IL-4, IL-4 receptor alpha, and Th2 cells.

Although IL-4-producing B cells (B effector 2 cells) are found following infection and immunization, the signals regulating IL-4 production by Be2 cells are unknown. We show that culturing naive B cells with Th2 cells induces up-regulation of IL-4 in the B cells with a concomitant down-regulation of T-bet, IL-12Rbeta2, and IFN-gamma. Up-regulation of IL-4 in the Be2 cells is dependent on both T cells and IL-4 as IL-4Ralpha-deficient B cells primed with Th2 cells did not transcribe IL-4, and B cells primed in the presence of IL-4-deficient Th2 cells produced IFN-gamma instead of IL-4. Likewise, the in vivo development of IL-4-expressing B cells in a nematode infection model was dependent on both T cells and IL-4Ralpha-mediated signals. Thus, the differentiation of naive B cells into IL-4-expressing Be2 cells is regulated by a combination of T cell-dependent signals and the cytokine environment and this process is critically dependent upon the IL-4/IL-4R signaling pathway.

Animals↗
PubMed1998

Anti-leishmania effector functions of CD4+ Th1 cells and early events instructing Th2 cell development and susceptibility to Leishmania major in BALB/c mice.

Resistance and susceptibility to infection with the intracellular parasite, Leishmania major, are mediated by parasite-specific CD4+ Th1 and Th2 cells, respectively. It is well established that the protective effect of parasite-specific CD4+ Th1 cells is largely dependent upon the IFN-gamma produced. However, recent results indicate that the effect of Th1 cells on resolution of lesions induced by L. major in genetically resistant mice also requires a functional Fas-FasL pathway of cytotoxicity. In contrast to resistant mice, susceptible BALB/c mice develop aberrant Th2 responses following infection with L. major and consequently suffer progressive disease. These outcomes clearly depends upon the production of interleukin 4 (IL-4) early after infection. We have shown that a burst of IL-4 mRNA, peaking in draining lymph nodes of BALB/c mice 16 hrs after infection, occurs within CD4+ T cells that express V beta 4-V alpha 8 T cell receptors. In contrast to control and V beta 6-deficient mice, V beta 4-deficient BALB/c mice were resistant to infection, demonstrating the role of these cells in Th2 development. The early IL-4 response was absent in these mice, and Th1 responses occurred following infection. The LACK antigen of L. major induced comparable IL-4 production in V beta 4-V alpha 8 CD4+ T cells. Thus, the IL-4 required for Th2 development and susceptibility to L. major is produced by a restricted population of V beta 4-V alpha 8 CD4+ T cells after cognate interaction with a single antigen from this complex parasite. The IL-4 produced rapidly by these CD4+ T cells induces within 48 hours a state of unresponsiveness to IL-12 among parasite-specific CD4+ T cell precursors by downregulating the IL-12 receptor beta 2 chain expression.

Animals↗
PubMed2005

Role for IL-4 nonproducing NKT cells in CC-chemokine ligand 2-induced Th2 cell generation.

NKT cells from C57Bl/6 mice are known to be the initial cellular source of IL-4 that acts as a trigger for Th2 cell differentiation. CC-chemokine ligand 2 (CCL2) has been described as an initial stimulator of IL-4 production by these cells; however, IL-4 was not produced by NKT cells from BALB/c mice even when Th2 cell responses were established in these mice. In this study, we found a new pathway for CCL2-associated Th2 cell generation in BALB/c mice. Splenic T cells from BALB/c mice produced IL-4 in response to CCL2 stimulation. However, IL-4 production was not seen in cultures of splenic T cells from CD1-/- mice (BALB/c origin), whereas, in the presence of CCL2, splenic T cells from CD1-/- mice produced IL-4 when NKT cells from wild-type mice were added. CCL2 induced IL-4 in cultures of NKT cells cocultured with naive T cells, but IL-4 was not produced by these cells cultured separately with CCL2. Interestingly, IL-4 was produced by naive T cells cocultured with NKT cells that were previously treated with CCL2 (CCL2-NKT cells). In addition, IL-4 was produced by naive T cells supplemented with a culture supernatant of CCL2-NKT cells. These results indicate that, through the production of a soluble factor(s) other than IL-4, NKT cells play a role in the CCL2-associated generation of Th2 cells.

Animals↗
PubMed2005

Induction of surface CCR4 and its functionality in mouse Th2 cells is regulated differently during Th2 development.

T helper cell type 1 (Th1) and Th2 cells express distinct sets of chemokine receptors. In contrast to Th1 chemokine receptors, it is largely unknown how Th2 chemokine receptors such as CC chemokine receptor 4 (CCR4) are induced during Th2 differentiation. Here, we investigated the induction of CCR4 surface expression and ligand responsiveness evaluated by functional assays such as chemokine binding and chemotaxis. This was done in comparison with those of a Th1 chemokine receptor, CXC chemokine receptor 3 (CXCR3). Resting T cells expressed neither CXCR3 nor CCR4. CXCR3 expression and ligand responsiveness were observed when resting T cells were stimulated with anti-CD3 plus anti-CD28 in the presence of [interleukin (IL)-12+anti-IL-4] and then recultured without T cell receptor (TCR) stimulation. Unlike CXCR3, CCR4 was induced immediately after anti-CD3/anti-CD28 stimulation in the presence of (IL-4+anti-interferon-gamma+anti-IL-12). However, these CCR4-positive cells failed to exhibit chemokine binding and chemotaxis. Although the levels of surface CCR4 expression were not increased after the subsequent reculture in the absence of TCR stimulation, CCR4 responsiveness was induced in this stage of Th2 cells. The induction of CCR4 expression and the acquisition of CCR4 responsiveness did not occur in IL-4-deficient (IL-4(-/-)) and signal transducer and activator of transcription (STAT)6(-/-) T cells. CCR4 expression and functionality were regained in IL-4(-/-) but not in STAT6(-/-) T cells by the addition of recombinant IL-4. Although surface expression and functionality of CCR4 are induced depending on the IL-4/STAT6 signaling pathway, the present results indicate that the functionality of CCR4 does not correlate with CCR4 expression but emerges at later stages of Th2 differentiation.

Animals↗
PubMed1990

The action of interleukin-4 on antigen-specific IgG1 and IgE production by interaction of in vivo primed B cells and carrier-specific cloned Th2 cells.

The production of anti-trinitrophenyl (TNP) antibodies of different isotypes from in vivo primed B cells was studied using the plaque-forming cell method. It was shown that these B cells secrete anti-trinitrophenyl antibodies of different isotypes only in the presence of Th2 cells specific for keyhole limpet hemocyanin (KLH) and the hapten-carrier conjugate TNP-KLH. Lipopolysaccharide-stimulated primed B cells without cells from the Th2 clone did not produce anti-TNP-specific IgG1 or IgE antibodies even in the presence of the hapten-carrier antigen TNP-KLH. Supernatants from these Th2 clones cultured with antigen-presenting cells and the complete antigen were unable to activate primed B cells for antibody secretion. Cognate interaction between primed B cells and carrier-specific Th2 cells is a prerequisite for hapten-specific IgG1 or IgE production. Anti-IL-4 antibody inhibited secretion of anti-hapten IgE antibody. Therefore, for production of anti-hapten antibody of the IgE isotype IL-4 is also necessary.

Animals↗
PubMed2003

Replication at the level of reverse transcription of HIV-1SF2 strain in Th1 and Th2 cells.

It has been reported that Th2 cells better support replication of T-tropic HIV-1 strain than Th1 cells. We investigated at the level of reverse transcription the replication of T-tropic HIV-1SF2 strain in Th1 and Th2 cells. To determine the presence of the early (RU5), intermediate (gag) and full-length (LTR/gag) product of reverse transcription of virus RNA in Th1 and Th2 cells, we employed the PCR technique. Our results revealed that the early (RU5) product of reverse transcription was detectable 30 min after infection in Th2 cells and 1 h after infection in Th1 cells. The product of reverse transcription corresponding to the gag region of HIV-1 was detected in Th2 cells 2 h after infection, whereas the same fragment of viral DNA in Th1 cells was observed 4 h later. The full-length viral DNA was seen in Th2 cells 6 h after infection but the same time course was not detected in the Th1 cells. We also observed that higher efficiency of reverse transcription of viral RNA correlated with better replication of HIV-1SF2 in Th2 than Th1 cells. The higher concentration of p24 HIV-1 antigen in culture medium than cytoplasm of Th1 and Th2 cells confirmed the lack of restriction at the budding step of HIV-1SF2 replication in Th1 and Th2 cells. Our observation may confirm the suggestion that Th0/Th2 cell orientation supports at the reverse transcriptional level the replication of T-tropic HIV-1 strains, which accelerates the onset of AIDS symptoms.

Adult↗
PubMed2001

Distinct patterns of membrane microdomain partitioning in Th1 and th2 cells.

Here we show that activated Th1 and Th2 cells have distinct patterns of membrane compartmentalization into lipid rafts. TCR complex members are recruited efficiently to rafts and aggregate with rafts at the site of MHC/peptide contact in Th1 cells but not Th2 cells. TCR/raft association in Th1 cells is deficient in the absence of CD4, suggesting that CD4 aids recruitment of the TCR to rafts. We show differential utilization of rafts in Th1 and Th2 cells by cholesterol depletion studies, which alters calcium signaling in Th1 but not Th2 cells. Furthermore, Th2 cells have a decreased ability to respond to low-affinity peptide stimulation. These studies indicate that components of membrane microdomains are differentially regulated in functionally distinct CD4 T cells.

Animals↗
PubMed2000

Interferon alpha prevents spontaneous apoptosis of clonal Th2 cells associated with chronic hypereosinophilia.

A recent study identified a clonal expansion of CD3(-)CD4(+)cells secreting Th2-type cytokines in 4 patients with chronic hypereosinophilia. Because interferon alpha (IFN-alpha) is used in the therapy of the idiopathic hypereosinophilic syndrome, the effects of this cytokine on the survival of clonal Th2 cells isolated from the blood of 2 patients were determined. First, these cells displayed a high rate of spontaneous apoptosis on culture in cytokine-free medium and were also sensitive to Fas-mediated apoptosis induced by soluble Fas ligand. Addition of IFN-alpha or interleukin-2 (IL-2) to culture medium resulted in significant protection against spontaneous but not Fas-induced apoptosis. Although spontaneous apoptosis of the clonal Th2 cells was clearly associated with down-regulation of both bcl-2 and bcl-x(L) levels, IFN-alpha had no significant effect on the expression of these antiapoptotic proteins, whereas addition of IL-2 resulted in higher levels of bcl-2. On the other hand, IFN-alpha decreased the numbers of cells with disrupted mitochondrial transmembrane potential both during spontaneous apoptosis and after exposure to protoporphyrin IX. Thus, IFN-alpha might promote the survival of clonal Th2 cells, an effect that could be relevant to the therapeutic approach for patients with chronic hypereosinophilia caused by clonal expansion of Th2-type cells. (Blood. 2000;96:4285-4292)

Adult↗
PubMed2002

The IL-10-producing competence of Th2 cells generated in vitro is IL-4 dependent.

Previous studies have suggested that activation of CD4+ T cells in the presence of IL-10 results in the generation of a population of T cells, T regulatory 1 (Tr1) cells, that primarily produce IL-10 and TGF-beta, but not IL-4. The relationship between Tr1 cells and conventional Th2 cells remains unclear. We were not successful in our attempts to generate significant numbers of antigen-specific T cells that secreted IL-10, but not IL-4, by culture in the presence of IL-10. The small numbers of cells that produced IL-10 only were completely dependent on the presence of IL-4 for their generation. In a polyclonal model, the development of IL-10 only producers was completely dependent on the presence of signal transducer and activator of transcription 6. Studies with myelin basic protein-specific T cells derived from an IL-4-deficient mouse confirmed the absolute requirement for IL-4 for the generation of IL-10 producers under all culture conditions. These IL-10-producing Th2 cells failed to inhibit EAE in an adoptive transfer model and were pathogenic when transferred to immunodeficient mice. Collectively, our results raise doubts about the existence of a unique population of CD4+ regulatory T cells that can be generated by activation in the presence of IL-10.

Animals↗
PubMed2006

GATA-3 promotes Th2 responses through three different mechanisms: induction of Th2 cytokine production, selective growth of Th2 cells and inhibition of Th1 cell-specific factors.

Naïve CD4 T cells can differentiate into at least two different types of T helpers, Th1 and Th2 cells. Th2 cells, capable of producing IL-4, IL-5 and IL-13, are involved in humoral immunity against extracellular pathogens and in the induction of asthma and other allergic diseases. In this review, we summarize recent reports regarding the transcription factors involved in Th2 differentiation and cell expansion, including Stat5, Gfi-1 and GATA-3. Stat5 activation is necessary and sufficient for IL-2-mediated function in Th2 differentiation. Enhanced Stat5 signaling induces Th2 differentiation independent of IL-4 signaling; although it does not up-regulate GATA-3 expression, it does require the presence of GATA-3 for its action. Gfi-1, induced by IL-4, promotes the expansion of GATA-3-expressing cells. Analysis of conditional Gata3 knockout mice confirmed the critical role of GATA-3 in Th2 cell differentiation (both IL-4 dependent and IL-4 independent) and in Th2 cell proliferation and also showed the importance of basal GATA-3 expression in inhibiting Th1 differentiation.

Animals↗