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PubMed1991

A possible novel pathway of regulation by murine T helper type-2 (Th2) cells of a Th1 cell activity via the modulation of the induction of nitric oxide synthase on macrophages.

Murine peritoneal macrophages activated with interferon (IFN)-gamma and lipopolysaccharide (LPS) produce high levels of nitric oxide (NO) and are efficient in killing the intracellular protozoan parasites Leishmania major in vitro. Earlier studies have shown that NO, whose synthesis in murine macrophages is catalyzed by an inducible enzyme NO synthase, plays a major effector role in the host resistance against microbial infection. We now shown that both the NO synthesis and the leishmanicidal activity can be inhibited by prior treatment of the cells with recombinant interleukin 4 (IL4). IL4 treatment had no effect on the binding of IFN-gamma to macrophages but prevented the induction of NO synthase in these cells activated with IFN-gamma and LPS. Since IFN-gamma is produced by murine T helper type-1 (Th1) cells, whereas IL4 is secreted by Th2 cells, these results suggest a novel pathway by which Th2 cells regulate an activity of Th1 cells, namely by inhibiting the induction of NO synthase. These results may also account for the mechanism by which the disease-promoting Th2 cells counteract the host-protective effect of Th1 cells in leishmaniasis and other intracellular parasitic diseases.

Amino Acid Oxidoreductases↗
PubMed2005

Epigenetic regulation of Th1 and Th2 cell development.

All cells of the body, regardless of the tissue type, contain the same genetic material, but express this genetic material differently. Epigenetics is one process by which differential gene expression within a cell is regulated. Epigenetic mechanisms involve postsynthetic modifications to DNA and/or DNA-associated histones that do not change the DNA sequence itself, but which remodel chromatin, are passed along at each cell division, and occur during and after early development. The CD4+ T cell best represents a cell in which epigenetic mechanisms are used to affect mature cell physiology. As a naïve CD4+ T cell develops into either a Th1 or Th2 cell that secretes predominantly IFN-gamma or IL-4, respectively, the expression of one cytokine gene and the permanent silencing of the other is orchestrated using epigenetic mechanisms. Because there appears to be an association between Th1/Th2 cell immunity, behavior, and/or disease, it is possible that an environmentally induced epigenetic change that occurs during Th1/Th2 cell development could explain how certain Th1/Th2-associated conditions develop. This article will review basic epigenetic mechanisms and what is known about how these mechanisms influence cytokine gene expression in a naïve CD4+ T cell as it develops into a Th1 or Th2 cell.

Animals↗
PubMed1999

Induction of a germinal center phenotype in B cells in vitro by a Th2 cell line.

We have investigated the contribution of various stimuli for generating in vitro the changes in surface phenotype characteristic of B cells responding to a T-dependent antigen in a germinal center (GC). We show that, unlike many other stimuli such as B cell mitogens, cytokines, and surrogate antigen, alone or in combination, an alloreactive Th2 clonal line induces splenic B cells to become cell surface peanut agglutinin (PNA)(hi), Ig(lo), CD62L(lo), and CD44(hi) to produce mRNA for M17 and to express a GC-specific transgene even without B cell receptor ligation. Neither proliferation nor prior activation of responding B cells is needed, but B cells from CD45-null mice show reduced efficiency of this induction. These findings open up possibilities for separation and dissection of the various components of the GC response.

Animals↗
PubMed2004

Requirements for the development of IL-4-producing T cells during intestinal nematode infections: what it takes to make a Th2 cell in vivo.

Components of the type 2 immune response may mediate host protection against both helminthic parasites and harmful allergic responses. A central player in this response is the T-helper 2 (Th2) effector cell, which produces interleukin (IL)-4, IL-5, IL-13, and other Th2 cytokines during the primary and memory response. Specific aspects of the parasite that trigger Th2-cell differentiation are not yet defined. Furthermore, the cell types and cell surface and secreted molecules that provide the immune milieu required for the development of Th2 effector cells and also Th2 memory cells are not well understood. They will probably vary with the particular helminth or other antigen inducing the Th2 response. We have used third stage larvae of intestinal nematode parasites as adjuvants to promote naïve nonparasite antigen-specific T cells to differentiate into Th2 cells. This model system avoids possible parasite antigen-specific T-cell clones or cross-reactive memory T cells that may preferentially differentiate into Th2 effector cells during the course of infection and confound the stereotypical components of parasite-induced Th2 cell differentiation. We have found that these parasites have a potent adjuvant effect and have used our model system to begin to investigate the events that lead to the development of polarized Th2 cells in vivo.

Animals↗
PubMed1998

Selective expression and functions of interleukin 18 receptor on T helper (Th) type 1 but not Th2 cells.

Interleukin (IL)-18 induces interferon (IFN)-gamma synthesis and synergizes with IL-12 in T helper type 1 (Th1) but not Th2 cell development. We report here that IL-18 receptor (IL-18R) is selectively expressed on murine Th1 but not Th2 cells. IL-18R mRNA was expressed constitutively and consistently in long-term cultured clones, as well as on newly polarized Th1 but not Th2 cells. IL-18 sustained the expression of IL-12Rbeta2 mRNA, indicating that IL-18R transmits signals that maintain Th1 development through the IL-12R complex. In turn, IL-12 upregulated IL-18R mRNA. Antibody against an IL-18R-derived peptide bound Th1 but not Th2 clones. It also labeled polarized Th1 but not Th2 cells derived from naive ovalbumin-T cell antigen receptor-alphabeta transgenic mice (D011.10). Anti-IL-18R antibody inhibited IL-18- induced IFN-gamma production by Th1 clones in vitro. In vivo, anti-IL-18R antibody reduced local inflammation and lipopolysaccharide-induced mortality in mice. This was accompanied by shifting the balance from Th1 to Th2 responses, manifest as decreased IFN-gamma and proinflammatory cytokine production and increased IL-4 and IL-5 synthesis. Therefore, these data provide a direct mechanism for the selective effect of IL-18 on Th1 but not Th2 cells. They also show that the synergistic effect of IL-12 and IL-18 on Th1 development may be due to the reciprocal upregulation of their receptors. Furthermore, IL-18R is a cell surface marker distinguishing Th1 from Th2 cells and may be a therapeutic target.

Animals↗
PubMed2002

The early IL-4 response to Leishmania major and the resulting Th2 cell maturation steering progressive disease in BALB/c mice are subject to the control of regulatory CD4+CD25+ T cells.

Susceptibility and development of Th2 cells in BALB/c mice infected with Leishmania major result from early IL-4 production by Vbeta4Valpha8 CD4+ T cells in response to the Leishmania homolog of mammalian RACK1 Ag. A role for CD4+CD25+ regulatory T cells in the control of this early IL-4 production was investigated by depleting in vivo this regulatory T cell population. Depletion induced an increase in the early burst of IL-4 mRNA in the draining lymph nodes of BALB/c mice, and exacerbated the course of disease with higher levels of IL-4 mRNA and protein in their lymph nodes. We further showed that transfer of 10(7) BALB/c spleen cells that were depleted of CD4+CD25+ regulatory T cells rendered SCID mice susceptible to infection and allowed Th2 differentiation while SCID mice reconstituted with 10(7) control BALB/c spleen cells were resistant to infection with L. major and developed a Th1 response. Treatment with a mAb against IL-4 upon infection with L. major in SCID mice reconstituted with CD25-depleted spleen cells prevented the development of Th2 polarization and rendered them resistant to infection. These results demonstrate that CD4+CD25+ regulatory T cells play a role in regulating the early IL-4 mRNA and the subsequent development of a Th2 response in this model of infection.

Adoptive Transfer↗
PubMed2001

How to deal with polarized Th2 cells: exploring the Achilles' heel.

The central effector cells in the pathogenesis of atopic allergic diseases are type 2 T helper (Th2) cells, which display an aberrant cytokine profile dominated by type 2 cytokines. Initial reports from mouse studies indicated that established and committed Th2 cells are stable and unsusceptible to modulation. However, there is a growing awareness that in humans, established effector Th2 cells are more flexible and can be reverted to predominant Th1 phenotypes. In fact, the Th1-driving cytokine interleukin (IL)-12 is the crucial factor in this respect. IL-12 is mainly produced by dendritic cells (DC), which can be primed for high or low IL-12 production, depending on inflammatory and/or microbial signals they encounter during their residence in the peripheral tissues. Accordingly, both the regulation of and the priming for IL-12 production in DC form ideal targets for therapeutic intervention. The development of new therapies for atopic allergy now focuses on local IL-12-promoting substances to target both the development of new Th2 cells and the persistent population of established allergen-specific Th2 cells.

Animals↗
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↗
PubMed2003

Dichotomy of autoreactive Th1 and Th2 cell responses to desmoglein 3 in patients with pemphigus vulgaris (PV) and healthy carriers of PV-associated HLA class II alleles.

Pemphigus vulgaris (PV) is the most severe autoimmune bullous skin disorder and is primarily associated with circulating autoantibodies (autoAb) against desmoglein 3 (Dsg3). In light of recent evidence that autoreactive T cells are critical for the induction and regulation of Ab production, the goal of this study was to characterize and quantitate autoreactive T cells in patients with PV and healthy controls. Peripheral Dsg3-reactive Th cells from 28 patients with acute-onset, chronic active, and remittent PV were quantitated by MACS secretion assay. Dsg3-reactive Th2 cells were detected at similar frequencies in all studied PV patients, while the number of autoreactive Th1 cells exceeded those of Th2 cells in chronic active PV. In contrast, healthy carriers of the PV-associated HLA class II alleles, DRB1*0402 and DQB1*0503, exhibited exclusively Dsg3-reactive Th1 cell responses, while healthy carriers of other HLA class II alleles did not. Moreover, the presence of IgG1 and IgG4 against Dsg3 was directly related to the ratio of Dsg3-reactive Th1/Th2 cells. T cell recognition of Dsg3 was restricted by HLA-DRB1*0402 and DQB1*0503 in PV patients and Dsg3-responsive healthy donors. These observations strongly suggest 1) that the appearance of Dsg3-reactive Th2 cells is restricted to patients with PV; 2) that specific HLA class II alleles that are prevalent in PV are critical for T cell recognition of Dsg3 in PV patients and Dsg3-responsive healthy donors; and 3) that autoAb production is associated with both Th1 and Th2 cells.

Acute Disease↗
PubMed1995

In vivo activity and in vitro specificity of CD4+ Th1 and Th2 cells derived from the spleens of diabetic NOD mice.

CD4+ T cell lines were generated from the spleens of diabetic NOD mice against crude membrane preparations derived from a rat insulinoma. Adoptive transfer of these lines into neonatal mice confirms that overt diabetes is induced by gamma-IFN-secreting Th1 cells, whereas transfer of IL-4-secreting Th2 cells resulted in a nondestructive peri-islet insulitis. Analysis of the antigens recognized by individual T cell clones from the Th1 line included reactivity against an insulinoma membrane fraction enriched in proteins of approximately 38 kD. Immune responses to the same antigen preparation have been associated with T cell clones derived from human insulin-dependent diabetes mellitus. The specificity of Th2 cells includes reactivity to a fraction enriched in proteins of 30 kD. The data suggest that in insulin-dependent diabetes mellitus the balance between beta cell destruction, associated with intra-islet infiltration, and nondestructive (potential protective) peri-islet insulitis may depend on both the antigens recognized, and the prevailing cytokine environment.

Animals↗
PubMedDate not supplied

An update on human Th1 and Th2 cells.

The existence of functionally polarized human T cell responses based on their profile of cytokine secretion in both the CD4+ T helper (Th) and the CD8+ T cytotoxic cell subset has been established. Human Th1 and Th2 cells not only produce a different set of cytokines but also exhibit distinct functional properties and preferential expression of some activation markers, such as LAG-3 and CD30, respectively. Several factors are involved in the Th cell differentiation into the polarized Th1 or Th2 pathway. They include the cytokine profile of 'natural immunity' evoked by different offending agents, the nature of the peptide ligand, as well as the activity of some costimulatory molecules and microenvironmentally secreted hormones, in the context of different host genetic backgrounds. Polarized Th1-type and Th2-type responses play different roles in protection, Th1 being effective in the defense against intracellular pathogens and Th2 against intestinal nematodes. Moreover, they are responsible for different types of immunopathological reactions. Th1 responses predominate in organ-specific autoimmune disorders, acute allograft rejection, unexplained recurrent abortions, and in some chronic inflammatory disorders of unknown etiology. In contrast, Th2 responses predominate in Omenn's syndrome, transplantation tolerance, chronic graft versus host disease, systemic sclerosis; moreover allergen-reactive Th2 cells are involved in the triggering of atopic disorders.

Autoimmune Diseases↗
PubMed2001

Clonal Th2 cells associated with chronic hypereosinophilia: TARC-induced CCR4 down-regulation in vivo.

We analyzed the expression of chemokine receptors on clonal Th2-type CD4(+)CD3(- )lymphocytes isolated from blood of two patients with chronic hypereosinophilia. First, we observed that these Th2 cells express membrane CCR5 and CXCR4 but neither CCR3 nor CCR4 when analyzed immediately after purification. However, CCR4 appeared following culture in human serum-free medium, suggesting that it was down-regulated in vivo. Indeed, patient's serum, but not control human serum, strongly down-regulated CCR4 expression on cultured Th2 cells. As high levels of TARC, a CCR4 ligand, were detected in the serum of four hypereosinophilic patients with CD3(-)CD4(+) clonal Th2 cells, we evaluated the effect of TARC neutralization in this system. Addition of a neutralizing anti-TARC mAb inhibited CCR4 down-regulation by patient's serum, indicating that circulating TARC contributed to CCR4 down-regulation on Th2 cells in vivo. Clonal Th2 cells did not secrete high levels of TARC themselves but induced a sustained production of TARC by monocyte-derived dendritic cells, a phenomenon that was inhibited by addition of blocking mAb against IL-4 receptor. We conclude that high circulating levels of TARC in serum of patients with chronic hypereosinophilia, most likely derived from antigen-presenting cells stimulated by Th2-type cytokines, induce down-regulation of CCR4 on Th2 cells in vivo.

Adult↗
PubMed2003

CC chemokine ligand 1 promotes recruitment of eosinophils but not Th2 cells during the development of allergic airways disease.

One of the characteristic features of allergic asthma is recruitment of large numbers of inflammatory cells including eosinophils and Th2 lymphocytes to the lung. This influx of inflammatory cells is thought to be a controlled and coordinated process mediated by chemokines and their receptors. It is thought that distinct, differential expression of chemokine receptors allows selective migration of T cell subtypes in response to the chemokines that bind these receptors. Th2 cells preferentially express CCR8 and migrate selectively to its ligand, CC chemokine ligand (CCL)1. We studied the role of the CCR8 ligand, CCL1, in the specific recruitment of Th2 cells and eosinophils to the lung in a murine model of allergic airway disease. We have demonstrated for the first time that CCL1 is up-regulated in the lung following allergen challenge. Moreover, a neutralizing Ab to CCL1 reduced eosinophil migration to the lung, but had no effect on recruitment of Th2 cells following allergen challenge. In addition, there was no change in airway hyperresponsiveness or levels of Th2 cytokines. In a Th2 cell transfer system of pulmonary inflammation, anti-CCL1 also failed to affect recruitment of Th2 cells to the lung following allergen challenge. Significantly, intratracheal instillation of rCCL1 increased recruitment of eosinophils but not Th2 cells to the lung in allergen-sensitized and -challenged mice. In summary, our results indicate that CCL1 is important for the pulmonary recruitment of eosinophils, rather than allergen-specific Th2 cells, following allergen challenge.

Adoptive Transfer↗
PubMed1992

IL-4 plays a dominant role in the differential development of Tho into Th1 and Th2 cells.

We have analyzed the evolution of the pattern of lymphokine secretion by Th cell lines specific for either the synthetic terpolymer Glu60Ala30Tyr10 (GAT) or killed bacillus Calmette Guérin. When cultured in the presence of exogenous rIL-2 as a growth factor, GAT-specific Th cell lines secreted mainly IL-4, whereas bacillus Calmette Guérin-specific lines produced predominantly IL-2. However, culturing in the presence of rIL-4 or of anti-IL-4 mAb and rIL-2 led to the establishment of Th2-like and Th1-like lines, respectively, regardless of their Ag specificity. Inasmuch as we show that the proliferative response of mature Th1 and Th2 cells was identical in the presence of IL-4, these results indicate that IL-4 influences the development of Th cell subsets. To understand the mode of IL-4 action, we isolated immature GAT-specific Tho clones able to secrete IL-2 and IL-4. Two types of Tho cells were isolated: ThoA cells that secreted IL-2 and IL-4, but not IFN-gamma, and ThoB cells that secreted IL-2, IL-4, and IFN-gamma. We show for the first time that such cells are indeed Th precursors able to differentiate into Th1 or Th2 cells. We demonstrate that IL-4 positively and negatively controls the differentiation of Tho cells into Th2 and Th1 cells, respectively. When cultured in rIL-4, Tho cells stop secreting IL-2 and IFN-gamma, but maintain IL-4 secretion. Moreover, endogenous IL-4 produced by Tho cells has similar effects: when cultured in rIL-2 alone, Tho cells either keep their immature phenotype or become Th2 cells, but do not become Th1 cells. In contrast, neutralization of secreted IL-4 completely prevents the differentiation of Tho into Th2 cells, but permits the development of Th1 cells. The presence of exogenous IFN-gamma does not affect the development of Tho into Th1 and Th2 cells, because it does not modify either mode of IL-4 action. However, it influences the ratio between the two types of Tho cells: when IL-4 is neutralized, added IFN-gamma can induce IFN-gamma secretion by ThoA cells and thereby facilitate their passage into ThoB cells. Taken together, our results demonstrate that IL-4, in addition to mediating T cell growth, is a principal factor that controls the differential development of Tho cells into Th1 and Th2 cells.

Animals↗
PubMed2005

PU.1 expression delineates heterogeneity in primary Th2 cells.

Primary T helper 2 cells are heterogeneous, expressing subsets of cytokines at varying levels. Mechanisms controlling this spectrum of phenotypes are still unclear. The ETS family transcription factor PU.1 is expressed in Th2 but not Th1 cells. Th2 cytokine production is decreased in cultures transduced with a PU.1-expressing retrovirus and increased in Th2 cells following RNAi that decreases PU.1 expression. In primary cultures, PU.1 expression is restricted to a subpopulation of Th2 cells that express CCL22 and a subset of Th2 cytokines. PU.1 regulates the Th2 phenotype by interfering with GATA-3 DNA binding without altering GATA-3 protein levels. Thus, the expression of PU.1 in subsets of Th2 cells establishes a defined cytokine profile and contributes towards establishing the spectrum of cytokine production observed in Th2 populations.

Animals↗
PubMed2005

Targeting memory Th2 cells for the treatment of allergic asthma.

Th2 memory cells play an important role in the pathogenesis of allergic asthma. Evidence from patients and experimental models indicates that memory Th2 cells reside in the lungs during disease remission and, upon allergen exposure, become activated effectors involved in disease exacerbation. The inhibition of memory Th2 cells or their effector functions in allergic asthma influence disease progression, suggesting their importance as therapeutic targets. They are allergen specific and can potentially be suppressed or eliminated using this specificity. They have distinct activation, differentiation, cell surface phenotype, migration capacity, and effector functions that can be targeted singularly or in combination. Furthermore, memory Th2 cells residing in the lungs can be treated locally. Capitalizing on these unique attributes is important for drug development for allergic asthma. The aim of this review is to present an overview of therapeutic strategies targeting Th2 memory cells in allergic asthma, emphasizing Th2 generation, differentiation, activation, migration, effector function, and survival.

Animals↗
PubMed2004

A distinct region of the murine IFN-gamma promoter is hypomethylated from early T cell development through mature naive and Th1 cell differentiation, but is hypermethylated in Th2 cells.

Reports on the status of DNA methylation of the IFN-gamma gene during T cell development in human and mouse have presented somewhat contradictory results. In this study we demonstrate in the mouse that methylation of the IFN-gamma promoter inhibits its transcriptional activity, and define a small hypomethylated region in T cells that correlates with transcription. The IFN-gamma promoter was also hypomethylated in NK cells, but not in B cells or nonhemopoietic tissues. Surprisingly, unlike the promoters of the IL-2 and IL-4 genes, the IFN-gamma promoter was hypomethylated in naive CD4(+) and CD8(+) T cells, and in this form from very early in T cell development. A population of non-B, non-T, non-NK cells containing the hypomethylated promoter was also found in the bone marrow. The hypomethylated state appears stable until peripheral CD4(+) T cells differentiate in response to Ag and APC. After T cell stimulation in vitro under Th2 conditions, but far less so under Th1 conditions, CD4(+) cells display a more methylated IFN-gamma promoter, which may contribute to the lack of expression of IFN-gamma in these preactivated cells. Our experiments support a new model of IFN-gamma chromatin structural changes in murine T cell development that differs from what has been previously published for human T cells.

Animals↗
PubMed1999

The absence of IL-6 does not affect Th2 cell development in vivo, but does lead to impaired proliferation, IL-2 receptor expression, and B cell responses.

The role of IL-6 in Th2 cell differentiation and response development after the injection of eggs from Schistosoma mansoni was investigated using wild-type (WT) and IL-6-/- mice. IL-6 was induced in the lymph nodes (LN) of WT mice within 24 h of egg injection, and IL-4 production by WT LN cells and CD4 T cells isolated 24 h after egg injection and stimulated in vitro was observed. In the absence of IL-6, this early production of IL-4 by LN cells and purified CD4 T cells was not abolished; although the level of IL-4 produced by IL-6-/- LN cells was similar to WT, IL-4 production by purified IL-6-/- CD4 T cells was reduced compared with WT. Despite the difference in CD4 T cell production of IL-4, the development of egg-specific Th2 cells 7 days after egg injection was not affected by the absence of IL-6. Nevertheless, Ab production was impaired and the in vitro proliferative response of whole LN cell populations, CD4 and CD8 T cells, and B cells from IL-6-/- mice was poor compared with WT. The proliferative defect in the IL-6-/- cells correlated with decreased IL-2R expression, and addition of exogenous IL-6 enhanced IL-2R expression as well as proliferation of LN cells from IL-6-/- mice. These studies demonstrate that Th2 differentiation and response development in vivo is not dependent on IL-6, but that Th-dependent and independent B cell responses are. Our results also emphasize the importance of IL-6 for lymphoproliferation, possibly through induction of IL-2R expression.

Animals↗