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PubMed2026

Th2 skewing in patients with disseminated coccidioidomycosis.

BACKGROUNDDisseminated coccidioidomycosis (DCM) is an often fatal and otherwise intractable condition requiring lifelong antifungal treatment. We have previously shown that a deranged polarization of CD4+ T cells toward a Th2 phenotype can exist in the context of DCM. Here, we studied a large population to determine the frequency of abnormal Th2 skewing of CD4+ T cells in patients with coccidioidomycosis and to identify underlying genetic mechanisms supporting this phenotype.METHODSWe collected PBMCs from 204 patients with coccidioidomycosis, including 96 patients with disseminated disease. We measured immune phenotypes and cytokine production by CD4+ T cells from patients and healthy controls, and comparisons between groups were made based on disease severity and demographics. Whole-genome sequencing was conducted on 180 individuals who also had cytokine profiling.RESULTSWe found that approximately 25% of patients with DCM had a CD4+ T cell compartment that was abnormally skewed toward a Th2 phenotype, and Th2 skewing was highly correlated with male sex. Coculture of T cells with the IL-4R/IL-13R-blocking antibody dupilumab reduced Th2 skewing. Sequencing revealed rare variants in genes involved in the IL-12/IFN-γ axis in several Th2-skewed patients, and we validated one such variant in IFNGR1 as hypomorphic.CONCLUSIONPatients with DCM, especially males, should be screened for Th2 skewing of CD4+ T cells. Patients with Th2 skewing should be additionally screened for genetic defects in the IL-12/IFN-γ axis. Our findings give a mechanistic rationale for blockade of IL-4R in Th2-skewed patients with refractory coccidioidomycosis.FUNDINGNational Institute of Allergy and Infectious Diseases/NIH grants R21 AI149654 and U19 AI166059 and University of California Office of the President grant VFR-19-633386.

Humans↗
PubMed1999

Allergen-specific Th1 cells fail to counterbalance Th2 cell-induced airway hyperreactivity but cause severe airway inflammation.

Allergic asthma, which is present in as many as 10% of individuals in industrialized nations, is characterized by chronic airway inflammation and hyperreactivity induced by allergen-specific Th2 cells secreting interleukin-4 (IL-4) and IL-5. Because Th1 cells antagonize Th2 cell functions, it has been proposed that immune deviation toward Th1 can protect against asthma and allergies. Using an adoptive transfer system, we assessed the roles of Th1, Th2, and Th0 cells in a mouse model of asthma and examined the capacity of Th1 cells to counterbalance the proasthmatic effects of Th2 cells. Th1, Th2, and Th0 lines were generated from ovalbumin (OVA)-specific T-cell receptor (TCR) transgenic mice and transferred into lymphocyte-deficient, OVA-treated severe combined immunodeficiency (SCID) mice. OVA-specific Th2 and Th0 cells induced significant airway hyperreactivity and inflammation. Surprisingly, Th1 cells did not attenuate Th2 cell-induced airway hyperreactivity and inflammation in either SCID mice or in OVA-immunized immunocompetent BALB/c mice, but rather caused severe airway inflammation. These results indicate that antigen-specific Th1 cells may not protect or prevent Th2-mediated allergic disease, but rather may cause acute lung pathology. These findings have significant implications with regard to current therapeutic goals in asthma and allergy and suggest that conversion of Th2-dominated allergic inflammatory responses into Th1-dominated responses may lead to further problems.

Allergens↗
PubMed2000

Th2 responses induced by epicutaneous or inhalational protein exposure are differentially dependent on IL-4.

Atopic individuals are predisposed to mounting vigorous Th2-type immune responses to environmental allergens. To determine the factors responsible, animal models that closely mimic natural modes of allergen exposure should prove most informative. Therefore, we investigated the role of IL-4, a known Th2-promoting cytokine, in generation of Th2 responses after exposure of either the skin or airway to soluble protein. Compared with wild-type (WT) mice, IL-4-deficient (IL-4(-/-)) mice showed markedly impaired Th2 activation after primary exposure to inhaled ovalbumin (OVA), with decreased OVA-specific IgG1 and IgE, and significantly fewer eosinophils in bronchoalveolar lavage (BAL) fluid after airway challenge. In contrast, IL-4(-/-) mice initially exposed to epicutaneous (e.c.) OVA mounted Th2 responses equivalent to responses in WT mice, with high numbers of eosinophils in BAL fluid. Because Th2 responses were not induced by e.c. OVA exposure in Stat6(-/-) mice (mice lacking signal transducer and activator of transcription 6), the role of IL-13 was tested. In vivo depletion of IL-13 prevented Th2 responses induced by e.c. OVA exposure in IL-4(-/-) mice. These data demonstrate a marked difference in the IL-4 dependence of Th2 responses generated at two anatomic sites of natural allergen encounter and identify the skin as a particularly potent site for Th2 sensitization.

Administration, Cutaneous↗
PubMed2000

Differential Ca2+ influx, KCa channel activity, and Ca2+ clearance distinguish Th1 and Th2 lymphocytes.

In Th1 and Th2 lymphocytes, activation begins with identical stimuli but results in the production of different cytokines. The expression of some cytokine genes is differentially induced according to the amplitude and pattern of Ca2+ signaling. Using fura- 2 Ca2+ imaging of murine Th1 and Th2 clones, we observed that the Ca2+ rise elicited following store depletion with thapsigargin is significantly lower in Th2 cells than in Th1 cells. Maximal Ca2+ influx rates and whole-cell Ca2+ currents showed that both Th1 and Th2 cells express indistinguishable Ca2+-release-activated Ca2+ channels. Therefore, we investigated other mechanisms controlling the concentration of intracellular Ca2+, including K+ channels and Ca2+ clearance from the cytosol. Whole-cell recording demonstrated that there is no distinction in the amplitudes of voltage-gated K+ currents in the two cell types. Ca2+-activated K+ (KCa) currents, however, were significantly smaller in Th2 cells than in Th1 cells. Pharmacological equalization of Ca2+-activated K+ currents in the two cell types reduced but did not completely eliminate the difference between Th1 and Th2 Ca2+ responses, suggesting divergence in an additional Ca2+ regulatory mechanism. Therefore, we analyzed Ca2+ clearance from the cytosol of both cell types and found that Th2 cells extrude Ca2+ more quickly than Th1 cells. The combination of a faster Ca2+ clearance mechanism and smaller Ca2+-activated K+ currents in Th2 cells accounts for the lower Ca2+ response of Th2 cells compared with Th1 cells.

Animals↗
PubMed2001

Allergen-specific Th1 cells counteract efferent Th2 cell-dependent bronchial hyperresponsiveness and eosinophilic inflammation partly via IFN-gamma.

Th2 T cell immune-driven inflammation plays an important role in allergic asthma. We studied the effect of counterbalancing Th1 T cells in an asthma model in Brown Norway rats that favors Th2 responses. Rats received i.v. transfers of syngeneic allergen-specific Th1 or Th2 cells, 24 h before aerosol exposure to allergen, and were studied 18-24 h later. Adoptive transfer of OVA-specific Th2 cells, but not Th1 cells, and OVA, but not BSA exposure, induced bronchial hyperresponsiveness (BHR) to acetylcholine and eosinophilia in a cell number-dependent manner. Importantly, cotransfer of OVA-specific Th1 cells dose-dependently reversed BHR and bronchoalveolar lavage (BAL) eosinophilia, but not mucosal eosinophilia. OVA-specific Th1 cells transferred alone induced mucosal eosinophilia, but neither BHR nor BAL eosinophilia. Th1 suppression of BHR and BAL eosinophilia was allergen specific, since cotransfer of BSA-specific Th1 cells with the OVA-specific Th2 cells was not inhibitory when OVA aerosol alone was used, but was suppressive with OVA and BSA challenge. Furthermore, recipients of Th1 cells alone had increased gene expression for IFN-gamma in the lungs, while those receiving Th2 cells alone showed increased IL-4 mRNA. Importantly, induction of these Th2 cytokines was inhibited in recipients of combined Th1 and Th2 cells. Anti-IFN-gamma treatment attenuated the down-regulatory effect of Th1 cells. Allergen-specific Th1 cells down-regulate efferent Th2 cytokine-dependent BHR and BAL eosinophilia in an asthma model via mechanisms that depend on IFN-gamma. Therapy designed to control the efferent phase of established asthma by augmenting down-regulatory Th1 counterbalancing mechanisms should be effective.

Administration, Inhalation↗
PubMed2001

Enforced expression of GATA-3 in transgenic mice inhibits Th1 differentiation and induces the formation of a T1/ST2-expressing Th2-committed T cell compartment in vivo.

The transcription factor GATA-3 is essential for early T cell development and differentiation of naive CD4(+) T cells into Th2 effector cells. To study the function of GATA-3 during T cell-mediated immune responses in vivo, we investigated CD2-GATA3-transgenic mice in which GATA-3 expression is driven by the CD2 locus control region. Both in the CD4(+) and the CD8(+) T cell population the proportion of cells exhibiting a CD44(high)CD45RB(low)CD62L(low) Ag-experienced phenotype was increased. In CD2-GATA3-transgenic mice, large fractions of peripheral CD4(+) T cells expressed the IL-1 receptor family member T1/ST2, indicative of advanced Th2 commitment. Upon in vitro T cell stimulation, the ability to produce IL-2 and IFN-gamma was decreased. Moreover, CD4(+) T cells manifested rapid secretion of the Th2 cytokines IL-4, IL-5, and IL-10, reminiscent of Th2 memory cells. In contrast to wild-type CD4(+) cells, which lost GATA-3 expression when cultured under Th1-polarizing conditions, CD2-GATA3-transgenic CD4(+) cells maintained expression of GATA-3 protein. Under Th1 conditions, cellular proliferation of CD2-GATA3-transgenic CD4(+) cells was severely hampered, IFN-gamma production was decreased and Th2 cytokine production was increased. Enforced GATA-3 expression inhibited Th1-mediated in vivo responses, such as Ag-specific IgG2a production or a delayed-type hypersensitivity response to keyhole limpet hemocyanin. Collectively, these observations indicate that enforced GATA-3 expression selectively inhibits Th1 differentiation and induces Th2 differentiation. The increased functional capacity to secrete Th2 cytokines, along with the increased expression of surface markers for Ag-experienced Th2-committed cells, would argue for a role of GATA-3 in Th2 memory formation.

Animals↗
PubMed2002

CD4 T cells selected by antigen under Th2 polarizing conditions favor an elongated TCR alpha chain complementarity-determining region 3.

The affinity of the MHC/peptide/TCR interaction is thought to be one factor determining the differentiation of CD4+ T cells into Th1 or Th2 phenotypes. To study whether CD4+ cells generated under conditions favoring Th1 or Th2 responses select structurally different TCRs, Th1 and Th2 clones and lines were generated from nonobese diabetic and nonobese diabetic H2-E transgenic mice against the peptides proteolipoprotein 56-70, glutamic acid decarboxylase(65) 524-543, and heat shock protein-60 peptides 168-186 and 248-264. Th1/Th2 polarization allowed the generation of clones and lines with fixed peptide specificity and class II restriction but differing in Th1/Th2 phenotype in which the impact on TCR selection and structure could be studied. The Th2 clones tended to use longer TCR complementarity-determining region (CDR)3alpha loops than their Th1 counterparts. This trend was confirmed by analyzing TCRalpha transcripts from Th1 and Th2 polarized, bulk populations. Molecular modeling of Th1- and Th2-derived TCRs demonstrated that Th2 CDR3alpha comprised larger side chain residues than Th1 TCRs. The elongated, bulky Th2 CDR3alpha loops may be accommodated at the expense of less optimal interactions between the MHC class II/peptide and other CDR loops of the TCR. We propose that CD4+ T cells selected from the available repertoire under Th2 polarizing conditions tend to have elongated TCR CDR3alpha loops predicted to alter TCR binding, reducing contact at other interfaces and potentially leading to impeded TCR triggering.

Amino Acid Sequence↗
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↗
PubMed2005

Indispensable role of Stat5a in Stat6-independent Th2 cell differentiation and allergic airway inflammation.

It is well-recognized that Stat6 plays a critical role in Th2 cell differentiation and the induction of allergic inflammation. We have previously shown that Stat5a is also required for Th2 cell differentiation and allergic airway inflammation. However, it is the relative importance and redundancy of Stat6 and Stat5a in Th2 cell differentiation and allergic airway inflammation are unknown. In this study we addressed these issues by comparing Stat5a-deficient (Stat5a(-/-)) mice, Stat6(-/-) mice, and Stat5a- and Stat6 double-deficient (Stat5a(-/-) Stat6(-/-)) mice on the same genetic background. Th2 cell differentiation was severely decreased in Stat6(-/-)CD4+ T cells, but Stat6-independent Th2 cell differentiation was still significantly observed in Stat6(-/-)CD4+ T cells. However, even in the Th2-polarizing condition (IL-4 plus anti-IFN-gamma mAb), no Th2 cells developed in Stat5a(-/-)Stat6(-/-) CD4+ T cells. Moreover, Ag-induced eosinophil and lymphocyte recruitment in the airways was severely decreased in Stat5a(-/-)Stat6(-/-) mice compared with that in Stat6(-/-) mice. These results indicate that Stat5a plays an indispensable role in Stat6-independent Th2 cell differentiation and subsequent Th2 cell-mediated allergic airway inflammation.

Animals↗
PubMed1999

Th2-induced airway mucus production is dependent on IL-4Ralpha, but not on eosinophils.

Mucus hyperproduction in asthma results from airway inflammation and contributes to clinical symptoms, airway obstruction, and mortality. In human asthmatics and in animal models, excess mucus production correlates with airway eosinophilia. We previously described a system in which TCR transgenic CD4 Th2 cells generated in vitro were transferred into recipient mice and activated in the respiratory tract with inhaled Ag. Th2 cells stimulated airway eosinophilia and a marked increase in mucus production, while mice that received Th1 cells exhibited airway inflammation without eosinophilia or mucus. Mucus could be induced by IL-4-/- Th2 cells at comparable levels to mucus induced by IL-4+/+ Th2 cells. In the current studies we dissect further the mechanisms of Th2-induced mucus production. When IL-4-/- Th2 cells are transferred into IL-4Ralpha-/- mice, mucus is not induced, and BAL eosinophilia is absent. These data suggest that in the absence of IL-4, IL-13 may be critical for Th2-induced mucus production and eosinophilia. To determine whether eosinophils are important in mucus production, IL-5-/- Th2 cells were transferred into IL-5-/- recipients. Eosinophilia was abolished, yet mucus staining in the epithelium persisted. These studies show definitively that IL-5, eosinophils, or mast cells are not essential, but signaling through IL-4Ralpha is critically important in Th2 cell stimulation of mucus production.

Administration, Inhalation↗
PubMed1995

Early activation signal transduction pathways of Th1 and Th2 cell clones stimulated with anti-CD3. Roles of protein tyrosine kinases in the signal for IL-2 and IL-4 production.

In the present experiments, TCR-CD3-associated early activation signal transduction pathways were examined in Th1 and Th2 clones by the stimulation with soluble monovalent anti-CD3 which resulted in efficient production of IL-2 and IL-4 in Th1 and Th2 cells, respectively. Although protein tyrosine kinases such as Fyn and ZAP-70 were activated in Th1 clones shortly after stimulation, these kinases in Th2 clones were not activated; but, their activity in resting conditions was shown to be decreased by the stimulation. In accordance with these findings, neither phospholipase C-gamma 1 activation nor phosphatidyl inositol-4,5-bisphosphate breakdown was induced in Th2 clones, in contrast to positive responses in Th1 clones. The oscillation of intracellular free Ca2+ concentration ([Ca2+]i) was a common signal for the activation of both Th1 and Th2 clones; however, the [Ca2+]i elevation in Th1 clones was herbimycin A sensitive, whereas that in Th2 was clone resistant, suggesting that the mechanism of the [Ca2+]i elevation in Th2 cells is different from that in Th1 cells in terms of the participation of protein tyrosine kinases. The anti-CD3 stimulation did not cause Lck activation in either the Th1 or Th2 clone, although remarkable activation was induced in both clones following anti-CD4 stimulation, indicating that Lck activation was not required for either IL-2 or IL-4 production of Th cells. Taken together, these results indicate that Th1 and Th2 cells are different from each other in early activation signal transduction pathways, especially in the role of protein tyrosine kinases.

Animals↗
PubMed1998

Activation of STAT proteins and cytokine genes in human Th1 and Th2 cells generated in the absence of IL-12 and IL-4.

We have shown previously that human CD4+ 45RO- T cells could be primed for a Th2 phenotype independent of IL-4 if they were activated by anti-CD28 mAb plus IL-2. If additional TCR signals were provided, the cells differentiated toward Th1 independent of IL-12. Here we show that anti-CD28/IL-2-primed Th2 cells expressed high levels of activated STAT6, but no cytokine mRNA. Moreover, both Th1 and Th2 cells expressed active STAT1 and -3, but not STAT2, -4, and -5. Restimulation of Th1 or Th2 cells via CD3 plus CD28 induced production of IFN-gamma or IL-4, respectively, but did not alter the activation status/DNA binding activity of STATs. Addition of IL-4 (or anti-IL-4 mAb) to restimulated Th2 cells did not modulate STAT6 activation or IL-4 expression, confirming the full commitment. However, Th2 cells remained responsive to IL-12, which repressed STAT6 DNA binding but activated STAT4, and this coincided with a suppression of IL-4/IL-5 and an induction of IFN-gamma. In Th1 cells, IL-12 activated both STAT6 and STAT4, and IL-4 activated STAT6, but in both cases the Th1 phenotype remained. Together the data show that CD28/IL-2-dependent Th2 priming activated STAT6 without inducing IL-4 expression. The primed Th cells resembled memory cells and produced IL-4 upon the first CD3/CD28 costimulus without detectable modulation of STATs. Th2 cells remained responsive to IL-12, which repressed STAT6 DNA binding and activated STAT4, and switched the cells to Th1. The effects of IL-12 may depend on the commitment of the cells, since IL-12 phosphorylated STAT6 in Th1 and dephosphorylated STAT6 in Th2 cells.

Cell Differentiation↗
PubMed1998

Beta 2-microglobulin-dependent T cells are not necessary for alloantigen-induced Th2 responses after neonatal induction of lymphoid chimerism in mice.

We have analyzed the requirement for beta 2-microglobulin (beta 2m)-dependent T cells in the generation of allogeneic Th2 responses in vivo. A neonatal injection of semiallogeneic cells in BALB/c mice induces a state of chimerism that promotes the differentiation of donor-specific CD4+ T cells toward the Th2 phenotype. Polyclonal T-B cell interactions occur in this model between host Th2 and donor B cells, resulting in the production of IgE Abs. IgE production and Th2-priming are critically dependent upon the early production of IL-4. Our data in the present paper demonstrate that: 1) IgE synthesis and the up-regulation of MHC class II and CD23 molecules on B cells are independent of beta 2m expression in the host, 2) no difference in the induction of CD4 alloreactive Th2 cells could be observed between beta 2m-/- and their wild-type control littermates when Th2-priming was measured in adult mice, and 3) the Th2 response and IgE production is induced in the complete absence of beta 2m-dependent T cells both in the host and in the inoculum. Therefore, using a variety of assays, we could not demonstrate diminished responses in mice with a disrupted beta 2m gene in this model of Th2-mediated allogeneic interaction, indicating that beta 2m-dependent NK1.1+ and CD8+ T cells are not required for the generation of alloreactive Th2 responses in vivo.

Animals↗
PubMed1992

Human Th1 and Th2 lymphocytes: their role in the pathophysiology of atopy.

In human beings, as in mice, two distinct patterns of cytokine secretion have been defined among CD4+ helper T-cell clones. Human type 1 helper (Th1), but not type 2 helper (Th2), cells produce interleukin-2 (IL-2), gamma-interferon (IFN-gamma), and tumor necrosis factor-beta, whereas Th2, but not Th1, cells secrete IL-4 and IL-5, but not IL-2 or IFN-gamma. Other cytokines, such as IL-3, IL-6, GM-CSF, or TNF-alpha, are produced by both Th1 and Th2 cells. Th0 cells, a third Th subset, show combined production of Th1- and Th2-type cytokines. The different cytokine patterns are associated with different functions. In general, Th2 cells provide an excellent helper function for B-cell antibody production, particularly of the IgE class. On the other hand, Th1 cells are responsible for delayed type hypersensitivity reactions and are cytolytic for autologous antigen-presenting cells, including B cells. Most allergen- or helminth-antigen-specific human CD4+ T-cell clones exhibit a Th2 phenotype, whereas most clones specific for bacterial antigens show a Th1 profile. Allergen-specific Th2 cells seem to play a crucial role in atopy. These cells induce IgE production via IL-4 and favor the proliferation, differentiation, and activation of eosinophils via IL-5. In addition, Th2-derived IL-3 and IL-4 are mast-cell growth factors that act in synergy, at least in vitro. Recent evidence indicates that allergen-specific Th2 cells are selectively enriched in tissues affected by allergic inflammation, such as the bronchial mucosa of subjects with allergic asthma.(ABSTRACT TRUNCATED AT 250 WORDS)

Allergens↗
PubMedDate not supplied

Effects of diesel exhaust particle extracts on Th1 and Th2 immune responses in mice.

The present study was undertaken to investigate the effects of extracts of diesel exhaust particles (DEP) on Th1 and Th2 immune responses. In order to separate compounds from DEP different in hydrophobicity, a single DEP sample was consecutively extracted with hexane (HEX-DEP), benzene (BEN-DEP), dichloromethane (DIC-DEP), methanol (MET-DEP), and 1M ammonia (AMM-DEP). The last unextracted residue (UNE-DEP) was also used to test its effect on immune responses. To immunize mice, hen egg lysozyme (HEL) was injected i.p. (day 0). Varying doses of DEP, each DEP extract, and UNE-DEP were intranasally administered every 2 days from days 0 to 18. Anti-HEL IgG2a antibodies in sera and IFN-γ secreted from spleen cells were measured as an indicator of Th1 immune responses, while anti-HEL IgG1 antibodies and IL-4 as that of Th2 responses. The results showed that treatment with DEP and DIC-DEP increased both Th1 and Th2 responses to HEL. UNE-DEP facilitated Th1 but not Th2 responses, while MET- and AMM-DEP administration was followed by enhancement of Th2 but not Th1 responses. Neither HEX- nor BEN-DEP modulated Th1 as well as Th2 responses. These results suggest that DEP contain various compounds different in hydrophobicity which may affect both Th1 and Th2, Th1 but not Th2, and Th2 but not Th1 immune responses.

Journal Article↗
PubMed1995

In vivo depletion of CD8+ T cells results in Th2 cytokine production and alternate mechanisms of allograft rejection.

A current hypothesis states that Th1 cytokines promote allograft rejection and that Th2 cytokines promote graft acceptance. We present data that question the tolerogenic activity of Th2 cytokines, and we suggest that Th2 cytokines may evoke allograft rejection by recruitment of alternate effector mechanisms. Unmodified rejection of mouse heterotopic cardiac allografts is associated with the accumulation of large numbers of donor-reactive CD8+ CTL within the allograft, which is indicative of a Th1-driven cellular response. However, when recipients are depleted of CD8+ CTL, rejection still occurs and is associated with an aggressive cellular infiltrate rich in eosinophils, large mononuclear cells, and fibroblast-like cells. Eosinophils, which are responsive to the Th2 cytokines IL-4 and IL-5, are not present in unmodified rejecting allografts. Differential production of Th1 versus Th2 cytokines was further suggested by altered levels of IgG2a (promoted by IFN gamma) and IgG1 (promoted by IL-4) alloantibody in the sera of these mice; IgG2a dominated the alloantibody response in unmodified allograft recipients, whereas IgG1 levels increased in recipients depleted of CD8+ CTL. Altered intragraft cytokine gene expression was verified by RT-PCR; Th1 (IL-2, IFN gamma), but not Th2 (IL-4, IL-5, IL-10), cytokine mRNAs were readily detectable in the allografts of unmodified recipients. In contrast, both Th1 and Th2 cytokine genes were expressed in the allografts of mice depleted of CD8+ CTL. These data suggest that donor-reactive CD8+ CTL inhibit intragraft production of Th2 cytokines, thereby promoting a Th1 dominated-rejection response. Elimination of CD8+ cells allows Th2 cytokine production, which may have deleterious, rather than protective, effects.

Animals↗
PubMed2000

IL-18 induces the differentiation of Th1 or Th2 cells depending upon cytokine milieu and genetic background.

The functional division of CD4(+) T cells into Th1 and Th2 subsets is generally accepted but the mechanisms leading to their preferential induction remain elusive. Cytokines are considered the main determining factors in the initial differentiation of precursor T cells into these distinct subsets. Thus, IL-12 drives Th1 cells whereas IL-4 drives Th2 cells. Recently IL-18, originally designated as IFN-gamma-inducing factor, has been reported to synergize with IL-12 in the induction of Th1 cells. We report here that IL-18 can also induce T cells to differentiate into Th2 cells, in the presence of TCR activation, either alone or together with IL-4. This effect of IL-18 is mediated primarily on CD4(+) T cells compared with CD8(+) T cells and is inhibited in the presence of IL-12. IL-18, however, has no effect on functionally committed Th2 cells.( )Moreover, the effect of IL-18 on Th2 cell development is differentially manifest in different mouse strains, suggesting profound underlying genetic influences. BALB/c mice infected with Leishmania major and treated with recombinant IL-18 developed exacerbated disease and enhanced Th2 response compared with untreated controls. These data therefore provide a novel mechanism for Th2 cell development. Thus, IL-18, a cytokine constitutively expressed by cells of the innate response, is capable of inducing Th2 cell differentiation in the absence of IL-4.

Animals↗
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↗