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PubMed1998

A pathogenic role of Th2 cells and their cytokine products on the pulmonary metastasis of murine B16 melanoma.

The role of Th2 cells and the cytokines produced by these cells on experimental pulmonary metastasis of B16 melanoma was investigated in a murine model implanted with high metastatic (B16F10) or low metastatic (B16F1) melanoma cells. An average of 250 colonies of metastasis in the lungs was counted in mice (BF10 mice) at 14 days after the inoculation of 2 x 10(5) B16F10 cells/mouse, while <20 colonies were detected in mice (BF1 mice) inoculated with the same number of B16F1 cells. CD4+ CD11b+ TCR-alphabeta+ T cells (BF10-Th2 cells) were produced in the spleens of BF10 mice, while these cells were not detected in BF1 mice. The BF10-Th2 cells produced IL-4 and IL-10 into culture fluids when stimulated in vitro with anti-CD3 mAb. However, IL-2 and IFN-gamma were not produced. The level of a pulmonary metastasis in BF1 mice increased to the level observed in BF10 mice, when BF10-Th2 cells were adoptively transferred to BF1 mice. Also, an increase in the number of pulmonary melanoma was demonstrated in BF1 mice treated with 10 microg/kg murine rIL-4. The level of pulmonary metastasis in BF10 mice or in BF1 mice inoculated with BF10-Th2 cells decreased to the level observed in BF1 mice when mice were treated with an anti-IL-4 mAb at a dose of 250 microg/kg on days 1, 3, and 5 after tumor inoculation. These results suggest that the severity of pulmonary metastasis in mice receiving B16 melanoma cells is strongly influenced by the IL-4 released from tumor-associated Th2 cells.

Adoptive Transfer↗
PubMed1992

Changes in expression of CD45R during the development of Th1 and Th2 cell lines.

Previous studies using anti-CD45R monoclonal antibodies (mAb) have shown that normal CD4+ T cells can be separated into virgin and memory cells based on their level of expression of CD45R. CD45Rhi (virgin) T cells secrete interleukin (IL)-2 whereas CD45Rlo (memory) T cells secrete both IL-2 and IL-4. In contrast to these results, studies using cultured T cell lines have shown that IL-2-secreting T helper cell type 1 (Th1) cells are CD45Rlo and IL-4-secreting Th2 cells are CD45Rhi. To resolve this discrepancy, and to determine how the Th1 and Th2 cell lines relate to memory CD45Rlo and virgin CD45Rhi CD4+ T cells, we have isolated CD45Rlo cells from alloantigen-primed mice and developed allospecific Th1 and Th2 cell lines. The lymphokines secreted by these lines were then evaluated. Our results show that as CD45Rlo T cells develop into in vitro cell lines which secrete IL-4, they become CD45Rhi. In contrast, CD45Rlo cells that develop into lines which secrete IL-2 maintain their CD45Rlo phenotype. Thus, although both Th1 and Th2 cells arise initially from CD45Rlo cells, Th2 cells become CD45Rhi during prolonged in vitro culture but, Th1 cells do not.

Animals↗
PubMed1995

Murine Th1 and Th2 cell clones differentially regulate macrophage nitric oxide production.

Previous studies have demonstrated that the combination of the T helper cell 1 (Th1)-derived cytokines interleukin (IL)-2 and interferon (IFN)-gamma induces nitric oxide (NO) production and tumor cytolysis by mouse peritoneal macrophages and the mouse macrophage cell line ANA-1 in vitro. Conversely, the Th2-derived cytokine IL-4 inhibits IL-2 and IFN-gamma-induced NO production and tumor cytolysis by ANA-1 macrophages. To examine the paracrine regulatory effects of Th1 and Th2 cells on macrophages, various mouse T cell clones were tested for their ability to regulate NO production by mouse peritoneal macrophages or ANA-1 macrophages. Antigen, superantigen, and mitogen stimulated Th1 cells but not Th2 cells induced NO production by macrophages. Supernatants from these activated Th1 clones also induced NO production by peritoneal macrophages and ANA-1 macrophages. Neutralization analysis using monoclonal anticytokine antibodies revealed that both IL-2 and IFN-gamma production by activated Th1 cells were required for the production of NO by macrophages. Co-culture studies using a panel of Th2 cell clones that share the same antigen specificity revealed that these cells suppressed Th1-mediated macrophage activation. The Th2-mediated impairment of Th1-induced NO production was primarily due to the secretion of IL-4. IL-4 appeared to have a direct effect on macrophage activation because neither mitogen-induced proliferation of Th1 cells nor cytokine production by Th1 cells were affected by IL-4. Overall, these results suggest that a potent paracrine regulatory network involving Th1 cells and Th2 cells may control the activation of macrophages for NO production and antitumor cytotoxicity.

Animals↗
PubMed2001

Functional plasticity of the LACK-reactive Vbeta4-Valpha8 CD4(+) T cells normally producing the early IL-4 instructing Th2 cell development and susceptibility to Leishmania major in BALB / c mice.

Early production of IL-4 by LACK-reactive Vbeta4-Valpha8 CD4(+) T cells instructs aberrant Th2 cell development and susceptibility to Leishmania major in BALB / c mice. This was demonstrated using Vbeta4(+)-deficient BALB / c mice as a result of chronic infection with MMTV (SIM), a mouse mammary tumor virus expressing a Vbeta4-specific superantigen. The early IL-4 response was absent in these mice which develop a Th1 response to L. major. Here, we studied the functional plasticity of LACK-reactive Vbeta4-Valpha8 CD4(+) T cells using BALB/ c mice inoculated with L. major shortly after infection with MMTV (SIM), i. e. before deletion of Vbeta4(+) cells. These mice fail to produce the early IL-4 response to L. major and instead exhibit an IFN-gamma response that occurs within LACK-reactive Vbeta4-Valpha8 CD4(+) T cells. Neutralization of IFN-gamma restores the production of IL-4 by these cells. These data suggest that the functional properties of LACK-reactive Vbeta4-Valpha8 CD4(+) T cells are not irreversibly fixed.

Animals↗
PubMed2002

Suppressors of cytokine signaling proteins are differentially expressed in Th1 and Th2 cells: implications for Th cell lineage commitment and maintenance.

Positive regulatory factors induced by IL-12/STAT4 and IL-4/STAT6 signaling during T cell development contribute to polarized patterns of cytokine expression manifested by differentiated Th cells. These two critical and antagonistic signaling pathways are under negative feedback regulation by a multimember family of intracellular proteins called suppressor of cytokine signaling (SOCS). However, it is not known whether these negative regulatory factors also modulate Th1/Th2 lineage commitment and maintenance. We show here that CD4(+) naive T cells constitutively express low levels of SOCS1, SOCS2, and SOCS3 mRNAs. These mRNAs and their proteins increase significantly in nonpolarized Th cells after activation by TCR signaling. We further show that differentiation into Th1 or Th2 phenotype is accompanied by preferential expression of distinct SOCS mRNA transcripts and proteins. SOCS1 expression is 5-fold higher in Th1 than in Th2 cells, whereas Th2 cells contain 23-fold higher levels of SOCS3. We also demonstrate that IL-12-induced STAT4 activation is inhibited in Th2 cells that express high levels of SOCS3 whereas IL-4/STAT6 signaling is constitutively activated in Th2 cells, but not Th1 cells, with high SOCS1 expression. These results suggest that mutually exclusive use of STAT4 and STAT6 signaling pathways by differentiated Th cells may derive in part, from SOCS3- or SOCS1-mediated repression of IL-12/STAT4- or IL-4/STAT6 signaling in Th2 and Th1 cells, respectively. Given the strong correlation between distinct patterns of SOCS expression and differentiation into the Th1 or Th2 phenotype, SOCS1 and SOCS3 proteins are therefore Th lineage markers that can serve as therapeutic targets for immune modulation therapy.

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

Th2 cells support intrinsic anti-inflammatory properties of the brain.

In experimental autoimmune encephalomyelitis (EAE), Th1 cells are responsible for disease induction while Th2 cells can be protective. To address the mechanisms of this differential behavior, we utilized organotypic murine entorhinal-hippocampal slice cultures to analyze interactions between myelin basic protein-specific Th1 and Th2 cells with microglial cells. While both Th1 and Th2 cells induced CD40 expression, only Th1 cells induced intercellular adhesion molecule-1 (ICAM-1) expression on microglia. Moreover, Th2 cells prevented or even reversed Th1-induced ICAM-1 upregulation. Evidently, Th2 cells could diminish Th1-induced inflammatory reactions and actively support the resting state of microglia, which could be one mechanism of Th2-mediated remission of neuroinflammation during EAE.

Animals↗
PubMed2002

Cutting edge: Th2 cell trafficking into the allergic lung is dependent on chemoattractant receptor signaling.

Th2 cells are recruited to the lung where they mediate the asthma phenotype. Since the molecular mechanisms regulating Th2 cell trafficking remain unknown, we sought to determine whether trafficking of Th2 cells into the lung is mediated by G alpha i-coupled chemoattractant receptors. We show here that in contrast to untreated Th2 cells, pertussis toxin-treated Th2 cells were unable to traffic into the lung, airways, or lymph nodes following Ag challenge and therefore were unable to induce allergic inflammation in vivo. Pertussis toxin-treated Th2 cells were functional cells, however, and when directly instilled into the airways of mice, bypassing their need to traffic to the lung, were able to induce airway eosinophilic inflammation. These studies conclusively demonstrate that trafficking of Th2 cells into the lung is an active process dependent on chemoattractant receptors.

Adoptive Transfer↗
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↗
PubMed2000

Antigen presentation to Th1 but not Th2 cells by macrophages results in nitric oxide production and inhibition of T cell proliferation: interferon-gamma is essential but insufficient.

The induction and role of nitric oxide (NO) during antigen presentation by macrophages to T helper (Th) cell subsets was examined. When cultured with Th1 clones, macrophage APC produced NO only in the presence of cognate Ag, which in turn suppressed T cell proliferation. IFN-gamma production by the activated Th1 cells was essential for the induction of NO. Th2 cells presented with the same cognate Ag did not induce NO production and proliferated uninhibited. Coactivation of Th1 and Th2 cells specific for the same Ag indicated that Th2 cells did not inhibit NO production, but were sensitive to NO induced by stimulated Th1 cells. Antigenic activation of Th2 cells in the presence of rIFN-gamma resulted in NO-mediated inhibition of proliferation. Th2 cells provided only a cell-associated cofactor, whereas Th1 cells secreted a soluble cofactor for IFN-gamma as well, i.e., TNF-alpha. Finally, a role for IFN-gamma and NO during immune responses was studied in spleen cells obtained from immunized IFN-gamma(-/-) mice. NO production and subsequent inhibition of Ag-specific proliferation ex vivo was observed only after the addition of rIFN-gamma. These studies suggest an IFN-gamma-dependent regulatory role for NO during Ag-specific Th cell activation involving macrophages, with obvious implications for Th subset-dependent immune responses in general.

Animals↗
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↗
PubMed1997

Human Th1 cells preferentially induce interleukin (IL)-1beta while Th2 cells induce IL-1 receptor antagonist production upon cell/cell contact with monocytes.

The role of human T cells in the induction and regulation, upon cell/cell contact, of inflammatory responses by monocytic cells was investigated. The production of interleukin (IL)-1beta and IL-1 receptor antagonist (IL-1Ra) by the monocytic THP-1 cell line was measured upon contact with either Th1 or Th2 cell clones. CD4+ T cell clones specific for purified protein derivative of Mycobacterium tuberculosis, predominantly Th1 [high interferon (IFN)-gamma and low IL-4 producers], or tetanus toxoid, predominantly Th2 (low IFN-gamma and high IL-4 producers), were generated. Cell membranes from antigen-stimulated, but not from resting T cell clones induced dose-dependent cytokine production by THP-1 cells. Th1 clones induced higher levels of IL-1beta production (484-806 pg/ml) than did Th2 clones (21-114 pg/ml). In contrast, Th1 clones induced lower levels of IL-IRa (0.9-7.8 ng/ml) than did Th2 clones (7.0-49.6 ng/ml). Similar results were obtained when T cell clones were activated by cross-linked CD3 and CD28. IL-1beta production by THP-1 cells correlated with IFN-gamma production by T cell clones but was unaffected by IFN-gamma neutralization. IL-1Ra production by THP-1 cells correlated with IL-4 production by T cells and was partially inhibited by IL-4 neutralization. These data indicate that activated Th1 and Th2 cells express different molecules on the cell surface able to induce distinct pro-inflammatory (IL-1beta) or anti-inflammatory (IL-1Ra) responses in monocytes. This differential induction of molecules with opposite effects on inflammation stresses the functional heterogeneity in CD4+ T cells.

CD28 Antigens↗
PubMed2002

Suplatast tosilate inhibits thymus- and activation-regulated chemokine production by antigen-specific human Th2 cells.

BACKGROUND: Suplatast tosilate is an anti-allergic agent that suppresses cytokine production by human Th2 cells. OBJECTIVE: We investigated the effects of suplatast tosilate on the production of thymus- and activation-regulated chemokine (TARC) by T cells from allergic patients with asthma. METHODS: Purified protein derivative (PPD)-specific Th1 cell lines and Dermatophagoides farinae (Der f)-specific Th2 cell lines were established from nine patients with house dust mite-allergic asthma. The effects of suplatast tosilate on mRNA expression of TARC and protein production of TARC from antigen-specific Th1 or Th2 cell lines were investigated after stimulation with relevant antigens or phytohemagglutinin (PHA). In addition, the effects of IL-4, IL-10, and IFN-gamma on TARC production by Der f-specific Th2 cell lines in the presence or absence of suplatast tosilate were studied. RESULTS: Although PPD-specific Th1 cell lines did not produce TARC after stimulation with PPD antigen or PHA, stimulation of Der f-specific Th2 cell lines with Der f antigen or PHA increased production of TARC. Suplatast tosilate significantly and dose-dependently inhibited production of TARC by Der f-specific Th2 cell lines stimulated with either Der f antigen (76.5% inhibition at 100 microg/mL, P < 0.01) or PHA (81.9% inhibition at 100 microg/mL, P < 0.01). TARC production by Der f-specific Th2 cell lines was significantly increased only by activation with IL-4 but not with IL-10 or IFN-gamma; this increase in TARC production was significantly inhibited by suplatast tosilate (97.5% inhibition at 100 microg/mL, P < 0.01). CONCLUSION: Suplatast tosilate inhibits TARC production by human Th2 cells. Therefore, this agent inhibits both Th2 cytokine and Th2 chemokine and may be a useful anti-allergic agent.

Adult↗
PubMed1996

Development in vitro of human CD4+ thymocytes into functionally mature Th2 cells. Exogenous interleukin-12 is required for priming thymocytes to produce both Th1 cytokines and interleukin-10.

Fresh postnatal thymocyte cell suspensions were directly cloned under limiting dilution conditions with either phytohemagglutinin or toxic shock syndrome toxin-1 (TSST-1), a bacterial superantigen. Cultures contained allogenic irradiated feeder cells and interleukin (IL)-2, in the absence or presence of exogenous IL-4, interferon (IFN)-gamma or IL-12. The resulting CD4+ T cell clones generated under these different experimental conditions were then analyzed for their ability to produce IL-2, IL-4, IL-5, IL-10, IFN-gamma and tumor necrosis factor (TNF)-beta in response to stimulation with phorbol 12-myristate 13-acetate (PMA) + anti-CD3 monoclonal antibody or PMA + ionomycin. Different from T cell clones generated from peripheral blood, virtually all CD4+ T cell clones generated from human thymocytes produced high concentrations of IL-2, IL-4 and IL-5, but no IFN-gamma, TNF-beta or IL-10. Moreover, after activation, these clones expressed on their surface membrane both CD30 and CD40 ligand, but not the product of lymphocyte activation gene (LAG)-3, and provided strong helper activity for IgE synthesis by allogeneic B cells. The Th2 cytokine pattern could not be modified by the addition of IFN-gamma. However, upon addition of exogenous IL-12, the resulting CD4+ thymocyte clones produced TNF-beta, IFN-gamma, and IL-10 in addition to IL-4 and IL-5. These results suggest that CD4+ human thymocytes have the potential to develop into cells producing the Th2 cytokines IL-4 and IL-5, whereas the ability to produce both Th1 cytokines and IL-10 is acquired only after priming with IL-12.

CD4-Positive T-Lymphocytes↗
PubMed2002

Pertussis toxin modulates the immune response to neuroantigens injected in incomplete Freund's adjuvant: induction of Th1 cells and experimental autoimmune encephalomyelitis in the presence of high frequencies of Th2 cells.

Pertussis toxin (PT) has been widely used to facilitate the induction of experimental autoimmune encephalomyelitis (EAE) in rodents. It has been suggested that this microbial product promotes EAE by opening up the blood-brain barrier and thereby facilitates the migration of pathogenic T cells to the CNS. However, PT has other biological effects that could contribute to its activity in EAE, such as enhancing the cytokine production by T cells and induction of lymphocytosis. In this work, we investigated the effects of PT on the pathogenicity, cytokine differentiation, and clonal sizes of neuroantigen-reactive T cells in EAE in mice. Our results show that PT prevented the protection from EAE conferred by injection of PLPp139-151 in IFA and induced high frequencies of peptide-specific Th1 cells and disease. Interestingly, the mice developed EAE despite the simultaneous vigorous clonal expansion of PLPp139-151-specific Th2 cells. The data indicate that the Th2 cells in this model neither were protective against EAE nor promoted the disease. Furthermore, the results suggested that the effects of the toxin on neuroantigen-reactive T cells were promoted by the PT-induced activation of APCs in lymphoid tissues and the CNS. Together, the results suggest that microbial products, such as PT, could contribute to the initiation of autoimmune disease by modulating the interaction between the innate and adaptive immune system in the response to self Ags.

Adoptive Transfer↗
PubMed1998

Differential localization of Th1 and Th2 cells in autoimmune gastritis.

The vast majority of CD4+ T cells infiltrating into gastric mucosa (GM) and in the draining (gastric) lymph node (GLN) shows an activated/memory phenotype, CD45RB(low) L-selectin(low) CD44(high), in neonataly thymectomized BALB/c mice bearing autoimmune gastritis (AIG), indicating that these cells are actively involved in this disease. CD4+ T cells sort-purified from GLN expressed mRNAs encoding for both IFN-gamma and IL-4. However, those infiltrating into GM expressed very low levels of IL-4 mRNA, even though they strongly expressed IFN-gamma mRNA. Among CD4+ T cells separated from AIG mice expressing detectable levels of either IFN-gamma or IL-4 by intracellular staining, less than one-seventh expressed IL-4 and thus most of them expressed IFN-gamma in GM, whereas roughly half and one-third expressed IL-4 in GLN and spleen respectively. These findings indicate that the Th1 cells predominantly infiltrate into autoimmune lesions and Th2 cells are mainly resident in the regional LN. We further set up an in vitro model system of transendothelial migration using a murine endothelial cell line, F-2, and found that Th1 cells in CD4+ T cells separated from lymphoid tissues of AIG mice preferentially passed through the monolayer of endothelial cells while only a small portion of Th2 cells did so. This differing ability of transendothelial migration and localization might explain the dominance of Th1 cells destroying the tissue in focal lesions without inhibition by the Th2 cells, in spite of both subsets being simultaneously activated in AIG mice, and the functions of each T cell subset seems to be mutually exclusive.

Animals↗
PubMed2003

Kinetics and STAT4- or STAT6-mediated regulation of genes involved in lymphocyte polarization to Th1 and Th2 cells.

Many genes implicated in Th1 and Th2 differentiation have been identified in both human and mouse. However, the functional roles and hierarchy of these factors in the signaling pathways leading to either Th1 or Th2 responses are less clear. To explore at which stage of polarization the differences between Th1 and Th2 cells occur, we have studied the expression of 23 key genes implicated in the process during the first week of polarization from human precursor T helper cells using quantitative real-time reverse transcription-PCR. According to our results, 14 of the genes were clearly regulated differentially in Th1 and Th2 conditions in distinct time-dependent patterns, either during the first 2 days or after 1 week of polarization. Furthermore, 6 of these genes were identified to be targets of STAT4/6 regulation. Thus, for the first time we demonstrate expression kinetics of a number of key genes involved in Th1 and Th2 differentiation during the first week of polarization in both human and mouse. In addition, our study shows for the first time that the genes BCL-6 and TRADD are differentially regulated during the polarization of human Th1 and Th2 cells.

Animals↗