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PubMed2005

Th2 induction by Nippostrongylus secreted antigens in mice deficient in B cells, eosinophils or MHC Class I-related receptors.

The populations of immune system cells necessary for induction of the Th2 response have yet to be fully defined. Among the most consistent natural stimuli for Th2 responses are helminth parasites, such as the gastrointestinal nematode Nippostrongylus brasiliensis. Strong Th2 bias in immune responsiveness to live parasite infection can be reproduced by injection of a soluble Nippostrongylus excretory/secretory product (NES) collected from adult worm parasites in vitro. Injection of soluble NES induces a residual type-2 response (IL-13) even in IL-4-deficient mice, and drives a fully polar Th2 response in IL-5-deficient animals. A potent IL-10 response is observed irrespective of IL-4 or IL-5 gene status. While MHC Class II knockout animals fail to mount any IL-4 or IL-10 response, the Th2 bias is intact in Class I knockouts, indicating that CD8+ or NK-like T cells restricted to classical or non-classical Class I molecules do not play an essential role in Th2 induction. B cell-deficient microMT animals also show responses, which are strongly skewed to IL-4 production. Thus, Th2 induction by Nippostrongylus antigens is independent of B cells, or MHC class I presentation, and does not require a sufficiency of eosinophils in vivo.

Animals↗
PubMed2004

Antigen stimulation of TH2 cells augments acute bacterial sinusitis in mice.

BACKGROUND: Previously, we showed that an ongoing nasal allergic response augmented bacterial sinusitis in mice. In those experiments mice were sensitized to ovalbumin (OVA) by means of intraperitoneal injections of OVA-alum and then exposed to OVA intranasally before being infected with Streptococcus pneumoniae. OBJECTIVE: We sought to study the importance of TH2 cells and to eliminate potential alum effects. METHODS: In this study we sensitized mice by adoptively transferring OVA-specific TH2- or TH1-skewed cells. RESULTS: TH2 passive sensitization followed by intranasal OVA showed a robust local eosinophilic response (5-fold increase) compared with that seen in mice with only TH2 passive sensitization alone (P <.001). Mice with TH2 passive sensitization and intranasal OVA exposure followed by infection showed an increase in the number of recovered S pneumoniae (P <.05) and an increase in sinus inflammation compared with that seen in those with infection alone (P <.01). In contrast, mice passively sensitized with TH1 followed by intranasal OVA exposure and infection showed no significant increase in the recovery of S pneumoniae and sinus inflammation compared with those with infection alone. CONCLUSIONS: These data support the importance of antigen-stimulated TH2 cells in the augmented response to infection in allergic mice. Whether the increased infection is related to the direct effect of TH2 cells and their cytokines or subsequent recruitment of other cells, such as eosinophils, will be determined in further studies.

Acute Disease↗
PubMed2005

P-selectin can support both Th1 and Th2 lymphocyte rolling in the intestinal microvasculature.

Lymphocyte localization to inflammatory sites is paramount for developing and maintaining an immune response. Rolling is the first step in recruitment, but our knowledge of its mechanisms in Th1 and Th2 CD4(+) lymphocytes is incomplete. Whereas initial studies suggested that Th1 but not Th2 lymphocytes used P-selectin for recruitment, more recent studies have proposed that both subtypes bind selectins. We used intravital microscopy to demonstrate in vivo that polarized Th1 and Th2 lymphocytes both use P-selectin to roll and adhere to cytokine [tumor necrosis factor (TNF)-alpha or interleukin (IL)-4]-activated intestinal microvasculature. The majority of Th1 lymphocyte flux in TNF-alpha- and IL-4-treated animals was P-selectin-dependent. Th1 lymphocytes also interacted with E-selectin to control rolling velocity after TNF-alpha stimulation. Th2 lymphocytes, which make IL-4 but not interferon-gamma, bound P-selectin ex vivo, with more than 95% rolling on P-selectin in vivo. Both Th1 and Th2 lymphocytes regulated rolling velocity by interacting with alpha(4)-integrin. Furthermore, in a model of spontaneous intestinal inflammation (ie, IL-10-deficient mice), both Th1 and Th2 lymphocytes rolled, adhered, and ultimately emigrated into the local microenvironment. These results suggest that both Th1 and Th2 lymphocytes use P-selectin in the initial rolling step in vivo in response to a global activator of the vasculature (TNF), a subtle inducer of P-selectin (IL-4), and pathological inflammation (IL-10-deficient mice).

Animals↗
PubMed2005

Both Th1 and Th2 cells require P-selectin glycoprotein ligand-1 for optimal rolling on inflamed endothelium.

The acquisition of homing receptors that redirect lymphocyte trafficking to nonlymphoid tissues after antigen encounter is a fundamental aspect of effector T-cell development. Although a role for selectins and their ligands has been well characterized for trafficking of Th1 cells to nonlymphoid sites, mechanisms responsible for Th2 trafficking are not well understood. Using a flow chamber system in which the endothelial interactions of two distinct T-cell populations could be examined simultaneously, we directly compared the requirements for Th1 and Th2 cell tethering and rolling. We found that although Th2 cells expressed significantly lower levels of selectin ligands than Th1 cells, activation of the endothelium by Th2-derived factors induced rolling interactions that were comparable for both Th1 and Th2 populations. Further, in the absence of PSGL-1, no other adhesion molecule could effectively compensate for lack of PSGL-1 to mediate rolling of either Th1 or Th2 cells. Thus, both Th1 and Th2 populations express functional PSGL-1-based selectin ligands for tethering and rolling on activated endothelium, and both effector populations can use PSGL-1 as the dominant scaffold for functional selectin ligand expression.

Animals↗
PubMed1999

Effect of suplatast tosilate (IPD-1151T) on cytokine production by allergen-specific human Th1 and Th2 cell lines.

Suplatast tosilate (IPD-1151T) is an antiallergic agent that suppresses airway eosinophil infiltration in asthma. We investigated the effects of IPD-1151T on proliferative response and cytokine production by human antigen-specific T cell lines. Purified protein derivatives (PPD)-specific T helper 1 (Th1) cell lines and Dermatophagoides farinae (Der f)-specific T helper 2 (Th2) cell lines were established from patients with asthma sensitized with house dust mite. Stimulation of PPD-specific and Der f-specific T cell lines with relevant antigens resulted in production of mostly interferon (IFN)-gamma and of interleukin (IL)-4 and IL-5, respectively. IPD-1151T did not inhibit the proliferative responses of either the Th1 or Th2 cell line to antigens. Although IPD-1151T did not inhibit IFN-gamma production by PPD-specific Th1 cell lines, it did inhibit IL-4 and IL-5 production by antigen-stimulated Der f-specific Th2 cell lines in a dose-dependent manner. IPD-1151T directly inhibited cytokine production by Der f-specific Th2 cell lines stimulated with immobilized anti-CD3 antibodies. Although IPD-1151T did not inhibit the clonal expansion of memory T cells among PBMCs into PPD-specific Th1 and Th2 cell lines, it did inhibit IL-4 and IL-5 production by Der f-specific Th2 cell lines but not IFN-gamma production by PPD-specific Th1 cell lines. These results suggest that IPD-1151T selectively inhibits Th2-type cytokine production.

Allergens↗
PubMed1997

The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells.

CD4 T cells potentiate the inflammatory or humoral immune response through the action of Th1 and Th2 cells, respectively. The molecular basis of the differentiation of these cells from naive T cell precursors is, however, unclear. We found that GATA-3 was selectively expressed in Th2 cells. GATA-3 is expressed at a high level in naive, freshly activated T cells and Th2 lineage cells, but subsides to a minimal level in Th1 lineage cells as naive cells commit to their Th subset. Antisense GATA-3 inhibited the expression of all Th2 cytokine genes in the Th2 clone D10. GATA-3 directly activated an IL-4 promoter-luciferase reporter gene in M12 cells. In transgenic mice, elevated GATA-3 in CD4 T cells caused Th2 cytokine gene expression in developing Th1 cells. Thus, GATA-3 is necessary and sufficient for Th2 cytokine gene expression.

Animals↗
PubMedDate not supplied

CD30 antigen: not a physiological marker for TH2 cells but an important costimulator molecule in the regulation of the balance between TH1/TH2 response.

Understanding the physiological role of CD30 would be an important step forward in transplants because CD30+ T cells can be induced by alloantigens even in the presence of immunosuppressives such as cyclosporine (Csa) and hence can act as regulatory cells in allograft. The results of functional studies on purified T CD30+ cell populations led us to hypothesize that the CD30 costimulator molecule is not a specific marker for TH2 cells in normal conditions, as has been suggested, but rather a marker for an important immunoregulatory subpopulation that regulates the balance between TH1 and TH2 (TH1/TH2) type response. To substantiate this hypothesis we studied the TH1/TH2 cytokine network in peripheral whole blood cultures stimulate with M44 CD30 ligand (CD30L), an agonistic monoclonal antibody (mAb). Four types of whole blood culture were used: the first had been stimulated with anti-CD3 mAb which generates a CD30 cytokine profile similar to alloreactive stimulation; the second with anti-CD3 mAb+M81 (an anti-CD30L mAb) to inhibit CD30/CD30L interaction; the third with anti-CD3+anti-interleukin (IL)4 mAbs to counteract IL4 activity and the fourth with anti-CD3+anti-interferon (IFN)gamma mAbs to counteract IFNgamma activity. Network interactions between soluble CD30 (sCD30, a maker of CD30 expression), sBcl2 (a marker of cell survival) and TH1/TH2 cytokines (IFNgamma, IL2, IL12p70, IL12p40, IL4, IL5 and IL10) were then studied in the supernatants obtained. Our results confirm the hypothesis above by showing that CD30 signals trigger functional mechanisms responsible for changes in levels of production of several important TH1 and TH2 cytokines involved in the regulation of the physiological balance between TH1/TH2 functions. The CD30-stimulated network, in fact, induces IFNgamma production linked to TH1 activity (-->TH1) which is subsequently integrated by IL4 production linked to TH2 activity (-->TH2). This production appears to be regulated, respectively, by IL12p40 (-->TH2) and IL12p70 (-->TH1) production which could maintain the balance between TH1/TH2 type response (TH1<-->TH2). Further CD30 mechanisms are the regulation of the interactions between: IL5-IFNgamma, IL5-IL4, IL2-IL10, IL2-IL12p40 and IL10-IL12p70 production. The immunoregulatory activity of CD30 was confirmed by the lack of production balance between the above-mentioned cytokines observed in cultures in which the interaction between CD30 and its natural ligand (CD30/CD30L) and IL4 or IFNgamma activity had been blocked. We therefore conclude that CD30 may be an important costimulatory molecule and marker for the physiological balance between TH1/TH2 immune response. Consequently, further study of CD30 immunoregulatory mechanisms may allow for the identification of methods for re-establishing equilibrium and hence more effective strategies for the prevention and treatment of immunopathological conditions such as transplant rejection.

Adult↗
PubMed2001

A critical role for NF-kappa B in GATA3 expression and TH2 differentiation in allergic airway inflammation.

The transcription factor GATA-3 is expressed in T helper 2 (TH2) but not TH1 cells and plays a critical role in TH2 differentiation and allergic airway inflammation in vivo. Mice that lack the p50 subunit of nuclear factor kappa B (NF-kappa B) are unable to mount airway eosinophilic inflammation. We show here that this is not due to defects in TH2 cell recruitment but due to the inability of the p50-/- mice to produce interleukin 4 (IL-4), IL-5 and IL-13: cytokines that play distinct roles in asthma pathogenesis. CD4+ T cells from p50-/- mice failed to induce Gata3 expression under TH2-differentiating conditions but showed unimpaired T-bet expression and interferon gamma (IFN-gamma) production under TH1-differentiating conditions. Inhibition of NF-kappa B activity prevented GATA-3 expression and TH2 cytokine production in developing, but not committed, TH2 cells. Our studies provide a molecular basis for the need for both T cell receptor and cytokine signaling for GATA-3 expression and, in turn, TH2 differentiation.

Animals↗
PubMed2003

Polarized Th1 and Th2 cells are less responsive to negative feedback by receptors coupled to the AC/cAMP system compared to freshly isolated T cells.

1. The adenylyl cyclase (AC)/cyclic adenosine monophosphate (cAMP) system is known to negatively regulate transcriptional activity of T cells, thereby possibly modulating T-cell-mediated responses at the sites of inflammation. Effects of cAMP have been widely studied in freshly isolated T cells and T-cell clones; yet, effects in differentiated Th1 and Th2 cells are largely unknown. 2. To obtain differentiated T helper cells, we activated naive T cells for 1 week in the presence of IL-12 plus alpha-IL-4 to generate Th1-type cells and in the presence of IL-4 plus alpha-IL-12 to generate Th2-type cells. 3. We demonstrate that, in contrast to freshly isolated T cells, the production of Th1 (IFN-gamma) and Th2 (IL-4, IL-5) cytokines in polarized T helper cells is not strictly controlled by the activation of AC/cAMP-linked beta(2)-adrenergic and prostaglandin (PG)E(2) receptors. 4. In Th2 cells, PGE(2) could still activate the G(s) protein-coupled AC/cAMP system and subsequently induce CREB phosphorylation, whereas PGE(2) was unable to activate the cAMP-dependent pathway in Th1 cells. In both Th1 and Th2 cells, the induction of CREB phosphorylation by beta(2)-agonist fenoterol was impaired. 5. The loss of control over cytokine production by cAMP elevating agents in differentiated Th1 and Th2 subsets may have important implications for the regulation of Th1- and Th2-mediated diseases, in particular those associated with the ongoing immune responses.

Adenylyl Cyclases↗
PubMed2003

Reciprocal expression of TRAIL and CD95L in Th1 and Th2 cells: role of apoptosis in T helper subset differentiation.

Upon activation, naïve T helper cells can differentiate into two major distinct subsets, T helper 1 (Th1) and T helper 2 (Th2), as defined by their effector functions and cytokine secretion patterns. Cytokine milieu and costimulatory molecules have been shown to play an essential role in determining T helper differentiation. However, it is still unclear how the effects of signals of costimulatory molecules and cytokines are exerted during T helper differentiation. We show evidence suggesting that while cytokine signals initiate the differentiation program, the selective action of death effectors determines the end point balance of differentiating T helper subsets. We examined the expression of TNF-related apoptosis-inducing ligand (TRAIL) and CD95L in cloned and in vitro differentiated Th1 and Th2 cells. We found that activation-induced expression of TRAIL is exclusively observed in Th2 clones and primary T helper cells differentiated under the Th2 condition, while the expression of CD95L is mainly in Th1 cells. Furthermore, these two subsets exhibit distinct susceptibilities to TRAIL- and CD95L-mediated apoptosis. Th2 cells are more resistant to either TRAIL- or CD95L-induced apoptosis than Th1 cells. More importantly, both Th1 and Th2 cells could induce apoptosis in labeled Th1 but not Th2 cells. Blocking TRAIL and CD95L significantly enhance IFN-gamma production in vitro. Likewise, young MRL/MpJ-lpr/lpr mice also showed more Th1 response to ovalbumin immunization as compared to MRL/MpJ+/+. Therefore, apoptosis mediated by CD95L and TRAIL is critical in determining the fate of differentiating T helper cells.

Animals↗
PubMed2003

TID1, a mammalian homologue of the drosophila tumor suppressor lethal(2) tumorous imaginal discs, regulates activation-induced cell death in Th2 cells.

We previously described two human DnaJ proteins, hTid-1L and hTid-1S, which are derived from alternative splicing of the TID1 gene, the human homologue of the Drosophila tumor suppressor lethal(2) tumorous imaginal discs, and showed that hTid-1L promoted while hTid-1S antagonized apoptosis. There are two subsets of helper T cells, Th1 and Th2, of which Th2 cells are significantly less prone to apoptosis induced by stimulation through the T-cell receptor. This apoptotic process is known as activation-induced cell death (AICD). The molecular basis for the differential susceptibility of Th1 and Th2 cells to AICD is not known. Here we show that the antiapoptotic variant, Tid-1S, is selectively induced in murine Th2 cells following activation. Expression of a dominant-negative mutant of hTid-1S in a Th2 cell line strikingly enhanced activation of caspase 3 in response to CD3 stimulation, and caused the cells to become sensitive to AICD. Hence, the accumulation of Tid-1S in Th2 cells following activation represents a novel mechanism that may contribute to the induction of apoptosis resistance during the activation of Th2 cells.

Amino Acid Sequence↗
PubMed2006

Simvastatin promotes Th2-type responses through the induction of the chitinase family member Ym1 in dendritic cells.

Statins, best known for their lipid-lowering actions, also possess immunomodulatory properties. Recent studies have shown a Th2-biasing effect of statins, although the underlying mechanism has not been identified. In this study, we investigated whether simvastatin can exercise a Th2-promoting effect through modulation of function of dendritic cells (DCs) without direct interaction with CD4+ T cells. Exposure of DCs to simvastatin induced the differentiation of a distinct subset of DCs characterized by a high expression of B220. These simvastatin-conditioned DCs up-regulated GATA-3 expression and down-regulated T-bet expression in cocultured CD4+ T cells in the absence of additional simvastatin added to the coculture. The Th2-biased transcription factor profile induced by simvastatin-treated DCs also was accompanied by increased Th2 (IL-4, IL-5, and IL-13) and decreased Th1 (IFN-gamma) cytokine secretion from the T cells. The Th2-promoting effect of simvastatin was found to depend on the chitinase family member Ym1, known to be a lectin. Anti-Ym1 antibody abolished the Th2-promoting effect of simvastatin-treated DCs. Also, simvastatin was unable to augment Ym1 expression in DCs developed from STAT6-/- or IL-4R alpha-/- mice. Thus, modulation of Ym1 production by DCs identifies a previously undescribed mechanism of Th2 polarization by statin.

Animals↗
PubMed1998

Prevention of Th2-mediated murine allergic airways disease by soluble antigen administration in the neonate.

It has been demonstrated recently that neonatal antigen administration in the mouse can lead to priming for Th2-mediated immune responses. This observation has important implications for the development of vaccination strategies in humans, particularly for individuals who may be predisposed to atopy or asthma. In this paper it is shown that although i.p. administration of antigen (100 microg) in adjuvant to the neonate does indeed prime for Th2-mediated disease in mice [allergic airways disease (AAD)], when the same relatively low dose of antigen is given in soluble form no priming occurs. Further, administration of a larger dose of soluble antigen (1 mg) actually prevents the ability to prime for a Th2 response subsequently and so prevents the induction of AAD. Protection from disease was associated with evidence of functional inactivation of both Th1 and Th2 ovalbumin-specific T cells. In contrast, administration of a very low dose of antigen (10 microg) primed for a Th2 response in a similar fashion to antigen in adjuvant. We suggest that the adjuvant lowers the "effective" dose of antigen administered in the neonate and thereby primes for Th2-type immune responses. These findings demonstrate that neonatal antigen administration can inhibit Th2-mediated diseases, such as AAD, but the dose of antigen may be critical to avoid predisposition to disease.

Animals↗
PubMed2003

The relative involvement of Th1 and Th2 associated immune responses in the expulsion of a primary infection of Heligmosomoides polygyrus in mice of differing response phenotype.

T helper cell (Th1 and Th2) associated responses were examined following a primary infection with the gastrointestinal nematode Heligmosomoides polygyrus in five inbred strains of mice with different resistance phenotypes. Levels of (i) mast cell protease, (ii) specific IgE, (iii) nitric oxide and (iv) specific IgG2a, as markers of Th2 and Th1 associated responses, respectively, were determined in sera and intestinal fluids and correlated with worm burdens. The "fast" responder (resistant) strains SWR and SJL produced strong Th2 and Th1 associated responses respectively in a mutually exclusive fashion. The F1 hybrid (SWRxSJL) F1, showed rapid expulsion of the parasite and expressed both intense Th1 and Th2 responses, suggesting synergism between Th1 and Th2 activity in these mice. The results indicate that both Th2 and Th1 responses operate in mice following a primary infection with H. polygyrus and that each Th response may be involved to a greater or lesser degree within certain strains. Resistance to H. polygyrus was found to correlate only to the intensity of either the gut-associated mastocytosis or nitric oxide production in these strains but not to either specific IgE or IgG2a titres. Chronic infections in the "slow" response phenotype mouse strains CBA and C57BL/10, were associated with both poor Th2 and poor Th1-associated responses attributed to a general parasite-mediated immunosuppression of the host immune response to infection.

Animals↗
PubMed1997

Behavior of visceral Leishmania donovani in an experimentally induced T helper cell 2 (Th2)-associated response model.

Although implicated in the clinical expression of human visceral leishmaniasis, a disease-exacerbating T helper cell 2 (Th2)-associated immune response involving interleukin-4 (IL-4) and/ or IL-10 is not readily detectable in experimental visceral infection. To overcome this obstacle to analyzing visceral Leishmania donovani in this relevant immunopathogenetic environment, we sought a model in which a Th2 response induces noncuring infection. Four initial approaches were tested primarily in BALB/c mice which control intracellular L. donovani via an IL-12- and interferon-gamma (IFN-gamma)-dependent Th1 mechanism: (a) modifying the cytokine milieu when the parasite is first encountered (treatment with exogenous IL-4 or anti-IL-12), (b) providing sustained endogenous exposure to a Th2 cytokine (infection of IL-4 transgenic mice), (c) increasing the parasite challenge inoculum, and (d) injecting heat-killed L. major promastigotes (HKLMP) to induce a cross-reactive Th2 response to live L. donovani. Only the last approach generated a functional Th2-type response that induced disease exacerbation accompanied by inhibition of tissue granuloma assembly. In HKLMP-primed BALB/c mice, prophylaxis with anti-IL-4, anti-IL-10, or exogenous IL-12 (but not IFN-gamma) readily restored resistance. In primed mice with established visceral infection, treatment with either IL-12 or IFN-gamma also successfully induced antileishmanial activity. The results in this model (a) suggest that rather than acting alone, IL-4 and IL-10 may act in concert to prevent acquisition of resistance to L. donovani, (b) reemphasize the capacity of IL-12 to reverse early Th2-related effects, and (c) demonstrate that Th1 cytokines (IL-12, IFN-gamma) have therapeutic action in an established systemic infection despite the presence of a disease-exacerbating Th2-type response.

Animals↗
PubMed1998

c-maf promotes T helper cell type 2 (Th2) and attenuates Th1 differentiation by both interleukin 4-dependent and -independent mechanisms.

The c-maf protooncogene is a T helper cell type 2 (Th2)-specific transcription factor that activates the interleukin (IL)-4 promoter in vitro. Although it has been postulated that c-maf directs the Th2-specific expression of the IL-4 gene in vivo, direct evidence that c-maf functions during the differentiation of normal, primary T cells is lacking. We now demonstrate that overexpression of c-maf in vivo skews the Th immune response along a Th2 pathway, as evidenced by increased production of Th2 cytokines and the IL-4-dependent immunoglobulins, IgG1 and IgE. The overproduction of IgGl and IgE in the CD4 promoter/c-maf transgenic mice was IL-4 dependent since this was not observed in c-maf transgenic mice bred onto an IL-4-deficient background. Ectopic expression of c-maf in mature Th1 cells did not confer on them the ability to produce IL-4, but did decrease the production of IFN-gamma. The attenuation of Th1 differentiation by c-maf overexpression occurred by a mechanism that was independent of IL-4 and other Th2 cytokines, and could be overcome by IL-12. These studies demonstrate that c-maf promotes Th2 differentiation by IL-4-dependent mechanisms and attenuates Th1 differentiation by Th2 cytokine-independent mechanisms.

Animals↗
PubMed2002

Th2 cell-specific cytokine expression and allergen-induced airway inflammation depend on JunB.

Naïve CD4+ T cells differentiate into effector T helper 1 (Th1) or Th2 cells, which are classified by their specific set of cytokines. Here we demonstrate that loss of JunB in in vitro polarized Th2 cells led to a dysregulated expression of the Th2-specific cytokines IL-4 and IL-5. These cells produce IFN-gamma and express T-bet, the key regulator of Th1 cells. In line with the essential role of Th2 cells in the pathogenesis of allergic asthma, mice with JunB-deficient CD4+ T cells exhibited an impaired allergen-induced airway inflammation. This study demonstrates novel functions of JunB in the development of Th2 effector cells, for a normal Th2 cytokine expression pattern and for a complete Th2-dependent immune response in mice.

Allergens↗
PubMed1996

TCR- and IL-1-mediated co-stimulation reveals an IL-4-independent way of Th2 cell proliferation.

Previously, it has been shown that Th1 cells, when triggered solely via their TCR, are blocked from proliferation in response to IL-2. Herein, we describe a similar characteristic for Th2 cells in that immobilized mAb directed to the TCR blocked proliferation of Th2 cells in response to IL-4. This "proliferative block' was observed in all four Th2 cell clones tested, but not in a subline of one of the clones which has been cultured in vitro for several years. Addition of IL-1 neutralized the proliferative block in all four Th2 cell clones. Surprisingly, blocking experiments with sIL-4R and anti-IL-4 mAb revealed that in three out of four Th2 cell clones this effect of IL-1 was IL-4-independent and could also not be blocked by cyclosporin A (CsA). In contrast, the proliferation of one Th2 cell clone in response to the TCR- and IL-1-mediated signals was indeed inhibited by sIL-4R, anti-IL-4 mAb and CsA. Thus, our data illustrate that in addition to the well-known IL-4-dependent proliferation, there also exists an IL-4-independent, IL-1-mediated way of Th2 cell proliferation.

Animals↗