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PubMed1998

Microglia are more efficient than astrocytes in antigen processing and in Th1 but not Th2 cell activation.

Microglia and astrocytes, two glial cell populations of the central nervous system, present Ag and stimulate T cell proliferation, but it is unclear whether they preferentially activate Th1 or Th2 responses. We have investigated the efficiency of microglia and astrocytes in the presentation of OVA peptide 323-339 or native OVA to Th1 and Th2 cell lines from DO11.10 TCR transgenic mice. Upon stimulation with IFN-gamma, microglia express MHC class II molecules, CD40, and ICAM-1 and efficiently present OVA 323-339, leading to T cell proliferation and production of IL-2 and IFN-gamma by Th1 and of IL-4 by Th2 cells. IFN-gamma-treated astrocytes, which express MHC class II and ICAM-1, present OVA 323-339 less efficiently to Th1 cells but are as efficient as microglia in inducing IL-4 secretion by Th2 cells. However, astrocytes are much less potent than microglia in presenting naturally processed OVA peptide to either T cell subset, indicating inefficient Ag processing. The capacity of astrocytes and microglia to stimulate Th1 and Th2 cells depends on their MHC class II expression and does not involve ICAM-1, B7-1, or B7-2 molecules. However, CD40-CD40L interactions contribute to Th1 activation by microglia. These data suggest that microglia may play a role in the activation of Th1 and Th2 cells, whereas astrocytes would restimulate mainly Th2 responses in the presence of appropriate peptides. This differential capacity of brain APC to restimulate Th1 and Th2 responses may contribute to the reactivation and regulation of local inflammatory processes during infectious and autoimmune diseases.

Animals↗

PubMed1998

[Flow cytometric analysis of helper T cell subsets (Th1 and Th2) in healthy adults].

To estimate frequency of T helper (Th) 1, Th2, and other related subsets in T cells among healthy Japanese, we determined the frequencies of interferon (IFN)-gamma- and/or interleukin (IL)-4-producing cells in stimulated peripheral blood lymphocytes (PBL) from 51 healthy adults of various ages by three-color flow cytometry using FITC-labeled anti-IFN-gamma, PE-conjugated anti-IL-4, and peridinin chlorophyll protein (PerCP)-labeled anti-CD4 or anti-CD3 antibody. As a result, proportions (mean +/- SD) of IFN-gamma-single positive (conveniently called Th1), IL-4-single positive (Th2), and double-positive cells (Th0) in CD4+ PBL, and homologous cell populations in CD3+ PBL (Th1 type, Th2 type, and Th0 type cells) were 21.3 +/- 8.2%, 2.7 +/- 1.1%, 1.9 +/- 1.0%, 39.5 +/- 13.5%, 1.7 +/- 0.8%, and 1.8 +/- 1.0%, respectively. Percentages of Th1 and Th2 were roughly consistent with those reported previously. Proportions of Th1, Th2, Th1 type, and Th2 type cells were found to increase with the age, whereas there were no significant difference in sex at least in 20s. Furthermore, positive correlation was seen between Th1 and Th1 type (r = 0.79), Th2 and Th2 type (r = 0.87), and Th0 and Th0 type (r = 0.86). Frequencies of these subsets in each donor were maintained at substantially the same levels for at least 3 months, suggesting existence of particular and stable Th1/Th2 balance among healthy individuals. As reported, 6 patients with atopic dermatitis examined in this study showed significantly lower frequencies of Th1 (11.0 +/- 2.5%) as compared with healthy donors (p < 0.01), implying usefulness of the immune test.

Adult↗

PubMed1992

Differences between T helper cell type I (Th1) and Th2 cell lines in signalling pathways for induction of contact-dependent T cell help.

B cells get help in the antibody response by presenting antigen to helper T (Th) cells. Upon antigen recognition, T cells produce lymphokines that act as growth and differentiation factors for B cells, but resting B cells require additional helper signals that depend on cell contact with an activated Th cell. Like lymphokine secretion, contact help must be induced by antigen recognition or antigen receptor cross-linking in continuous Th cell lines. In the mouse, most CD4+ T cell lines can be classified into one of two stable differentiation states, Th1 or Th2, which produce different lymphokines and have different effector functions, activation requirements and cytoplasmic signalling mechanisms. This report demonstrates additional differences between Th1 and Th2 cell lines in the signalling pathways leading from the T cell antigen receptor to the induction of Th functions. In a system dependent on antigen presentation by B cells, B cell proliferation driven by Th2 cells but not Th1 cells was blocked by acute treatment with phorbol esters. Further experiments showed that phorbol esters blocked the induction of both contact help and lymphokine production in Th2 cells but not in Th1 cells. However, depletion of protein kinase C (PKC) activity by prolonged treatment of T cells with high concentrations of phorbol esters blocked induction of contact help and lymphokine production in Th1 cells but not in Th2 cells. These findings support the hypothesis that Th2 cells use a signalling pathway that is independent of PKC and that PKC activation can block this pathway. Since contact help and lymphokine secretion are affected in parallel, this difference between Th1 and Th2 cells probably reflects early events in the signalling pathway. Contact help and lymphokine production could be dissociated with cholera toxin and other cAMP agonists, but this dissociation could be explained by non-cAMP-related effects of cholera toxin on induction of contact help in Th2 cells, and by the direct effect of cAMP agonists on interleukin 2 gene transcription in Th1 cells reported by other laboratories.

Animals↗

PubMed1991

Differential abilities of Th1 and Th2 to induce polyclonal B cell proliferation.

Human gamma globulin-specific T helper cell (Th) clones, activated by HGG in the presence of antigen (Ag)-presenting cells, stimulated polyclonal B cell proliferation. Both Th1 and Th2 clones induced B cell proliferation, but Th1 clones were generally 5- to 10-fold less efficient than Th2 in this capacity. Th1 and Th2 each induced proliferation of both small and large B cells, although Th1 induced less B cell proliferation than Th2, regardless of B cell size. Th1-induced B cell proliferation was increased significantly by stimulating the Th1 clones with immobilized anti-CD3 mAb. The B cell response to Ag-activated Th1 clones was also increased by the addition of rIL-4 or culture supernatants from activated Th2 clones, and this enhancement was abolished by addition of anti-IL-4 mAb. The differential capacity of the Th subsets to stimulate B cells could not be attributed to differences in the degree of Ag-induced activation of the Th clones as reflected by Th proliferation or Th expression of activation markers, RL388 Ag, IL-2R, or TfR. Taken together the results suggest that even though Th1 and Th2 are similarly activated by Ag-presenting cells, Ag-activated Th2 interact more effectively with B cells than Ag-activated Th1. It is possible that inefficient interaction and subsequent intercellular signaling between Th1 and B cells results in inefficient Th1-induced B cell proliferation, and that this deficiency may be circumvented by signals (e.g., lymphokines) provided by Th2, or by the stimulation of Th1 with plate-bound anti-CD3 Ab rather than Ag.

Animals↗

PubMedDate not supplied

Encephalitogenic Th1 cells are inhibited by Th2 cells with related peptide specificity: relative roles of interleukin (IL)-4 and IL-10.

Cytokines secreted by T-helper type 2 (Th2) cells inhibit the antigen-induced stimulation of type 1 (Th1) helper T cells. To study this form of regulation in an autoimmune disease model, the cytokines secreted by a Th2 clone specific for the encephalitogenic proteolipid protein (PLP) peptide 139-151 were tested for their ability to inhibit proliferation of an encephalitogenic Th1 clone specific for an epitope contained within the same peptide. Cytokines, produced by stimulation of the Th2 clone with CD3-specific monoclonal antibodies (mAbs), inhibited proliferation of the Th1 clone when stimulated by antigen and splenic antigen-presenting cells (APC). Inhibition was, however, not antigen-specific since cytokines released upon stimulation of an unrelated Th2 clone were also inhibitory. Inhibition was found to be caused by effects on either antigen presentation or co-stimulatory activity of the APC and not by direct effects on the Th1 cells. MAbs for the two major regulatory Th2 cytokines were used to identify the inhibitory component secreted by activated Th2 cells. Interleukin-10 (IL-10)-specific mAb abolished the inhibitory effect, while mAb specific for IL-4 had no effect on inhibition. The addition of recombinant IL-4 (rIL-4) and rIL-10 confirmed that inhibition of Th1 proliferation was due to secretion of IL-10 by the Th2 clone and its subsequent effects on APC. The studies described here demonstrate that PLP-specific Th2 cells which recognize peptide 139-151 inhibit encephalitogenic Th1 cells which respond to an epitope on the same peptide. This phenomenon may be important for local, antigen-specific regulation of inflammation in the central nervous system.

Animals↗

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↗

PubMed1994

IL-12 inhibits Th2 cytokine responses induced by eggs of Schistosoma mansoni.

In the mouse, infection with the helminth parasite Schistosoma mansoni results in the selective induction of CD4+ T lymphocytes belonging to the Th2 subset. Schistosome ova are responsible for the development of Th2 responses seen in patently infected animals and the injection of eggs s.c. into the footpad leads to the development of elevated Th2 cytokine production by T cells in the draining popliteal lymph node. Using the egg injection model, we have shown that IL-12 suppresses schistosome egg-induced Th2 responses as evidenced by decreased IL-4, IL-5, and IL-10 secretion in vitro while increasing the production of the Th1 cytokine IFN-gamma. Similar responses were obtained using either total lymph node cells or purified CD4+ T cells, indicating that IL-12 acts at the T cell level. When given as a single injection IL-12 was most effective at inhibiting Th2 responses when administered 2 days after egg inoculation, a time when T cells are still in a Th0 phase. The suppression of Th2 responses induced by IL-12 was blocked when the animals were simultaneously injected with neutralizing anti-IFN-gamma mAb, either systemically or systemically plus locally. Anti-IFN-gamma also inhibited the enhancement of IFN-gamma responses induced by IL-12 but only if the mAb was administered systemically plus locally. NK cells are likely to be a major source of the immunoregulatory IFN-gamma, because the effects of IL-12 on Th2 cytokine production were suppressed in mice treated with anti-asialo-GM1 Abs. Together these results suggest that IL-12 may have potential use in preventing or treating parasite-induced pathology resulting from Th2 cytokine production.

Animals↗

PubMed1993

Immortalization with herpesvirus saimiri modulates the cytokine secretion profile of established Th1 and Th2 human T cell clones.

T blasts of six established human CD4+ T cell clones with defined Ag specificity and cytokine secretion profile (3 Th1 and 3 Th2) were immortalized with Herpesvirus saimiri (HVS) and compared with their uninfected counterparts for their ability to proliferate, produce cytokines, and express cytolytic activity. HVS-transformed Th1 and Th2 clones neither substantially changed their original surface markers nor lose their ability to proliferate in response to their specific Ag but did acquire the ability to proliferate in response to contact signals delivered by SRBC or autologous APC alone. In addition, transformation by HVS substantially enhanced the lectin-dependent cytolytic activity of Th1 clones and enabled noncytolytic Th2 clones to exert cytolytic activity. HVS-transformed Th1 clones but not their uninfected counterparts spontaneously transcribed and secreted Th1-type cytokines (IL-2, IFN-gamma, and TNF-beta) and such a production was further enhanced by stimulation with either SRBC or PMA plus anti-CD3 mAb. HVS transformed but not uninfected Th2 clones constitutively expressed both IL-4 and IL-2 mRNA and secreted IFN-gamma. Stimulation with PMA plus anti-CD3 mAb induced uninfected Th2 clones to secrete high amounts of IL-4 and IL-5 but not Th1-type cytokines, whereas the same HVS-transformed Th2 showed minimal IL-4 and IL-5 secretion with concomitant high production of IL-2, IFN-gamma, and TNF-beta. Transformation by HVS also resulted in up-regulation of TNF-alpha and IL-3 production by both Th1 and Th2 clones. The ongoing proliferation of HVS-transformed clones was partially inhibited by either anti-IL-2 or anti-IL-3 antibodies and virtually abolished by the combined addition of the two anticytokine antibodies, suggesting that both IL-2 and IL-3 can function as autocrine growth factors for HVS-transformed Th1 and Th2 clones.

Cell Transformation, Viral↗

PubMed1993

Th2 cells mediate IL-4-dependent local tissue inflammation.

We investigated whether polyclonal murine Th1 and Th2 cells obtained after short term culture in vitro were capable of mediating tissue inflammation in vivo. Th cells were pulsed with mAb to the TCR/CD3 complex and injected into the footpads or ears of naive syngeneic recipient mice. Th1 induced delayed swelling that peaked at 24 to 48 h and lasted > or = 5 days. Th2-induced swelling peaked at 6 h and lasted < or = 48 h. Similar responses were also observed in athymic nude mice. Lesions with both Th1 and Th2 cells contained a predominant neutrophilic infiltrate at 6 h, and mainly mononuclear cells at 48 h. The inflammatory response with Th2 was blocked by cyclosporin A, by mAb to IL-4 or by soluble rIL-4R. The requirement for IL-4 was early and transient. Four alloreactive short term Th2 clones induced swelling in allogeneic recipients. mAb- and IL-4-dependent swelling responses were also observed with two long term Th2 clones. Our results demonstrate that Th2 cells mediate IL-4-dependent tissue inflammation, and strengthen the concept that Th2 cells play an important role in some T cell-dependent immune reactions and, possibly, in allergic disorders such as atopic dermatitis and allergic asthma.

Animals↗

PubMed2000

Impact of in utero Th2 immunity on T cell deviation and subsequent immediate-type hypersensitivity in the neonate.

It was the aim of this study to analyze the impact of maternal Th2 immune responses on onset and subsequent development of allergen-specific immunity and immediate-type hypersensitivity in early childhood. In a well characterized mouse model of Th2 immunity, BALB / c mice were sensitized to ovalbumin (OVA) before mating followed by allergen aerosol exposure during pregnancy. At the end of pregnancy mice developed allergen-specific Th2 / Th0 immunity and immediate-type hypersensitivity responses to OVA. T cells from these newborns, when restimulated with PMA / ionomycin, demonstrated a lowered capacity to produce IFN-gamma. To assess whether prenatal allergen exposure favors postnatal onset of a Th2-type immune response, these offspring were immunized to a novel antigen by a single injection of beta-lactoglobulin (BLG). In contrast to offspring from non-sensitized mothers, offspring from OVA-sensitized mice showed both higher anti-BLG immunoglobulin titers and higher frequencies of immediate-type skin test responses. Our data suggest that Th2 / Th0 immunity present during pregnancy has a decisive impact on shaping of the Th1 / Th2 T cell profile in the neonate. Furthermore, this effect favors the development of Th2 immune responses, when mice are exposed to a novel antigen during early childhood.

Animals↗

PubMed1995

Interleukin-12 increases interleukin-4 production by established human Th0 and Th2-like T cell clones.

Interleukin (IL)-12 is a potent inducer of cell-mediated immunity: it favors the generation of interferon (IFN)-gamma-producing T cells, increases IFN-gamma production by T cells and natural killer cells and prevents the generation of a Th2 response in murine in vivo models. Nevertheless, the effects of IL-12 on an established Th2 response remain poorly documented. In the present paper, we analyzed the effect of IL-12 on the profile of lymphokines produced by established IL-4-producing Th0 and Th2-like human T cell clones (TCC) and by polyclonal T cells. We found that IL-12 (i) enhances, as previously reported, IFN-gamma production by Th0 TCC and, to a smaller extent, by Th2-like TCC, (ii) increases the proliferation of Th0 and Th2-like TCC and (iii) unexpectedly, synergizes with T cell receptor-associated or nonspecific stimuli in increasing IL-4 production by these TCC. Thus, IL-12 potentiates the production of IFN-gamma and also of IL-4 by established IL-4 producing TCC. Although IL-12 has been widely reported to induce a Th1 response and to prevent the development of a Th2 response in vivo, IL-12 may on the contrary potentiate an established Th2 response in humans.

CD4-Positive T-Lymphocytes↗

PubMed2003

OX40 (CD134) and OX40 ligand interaction plays an adjuvant role during in vivo Th2 responses.

The role of OX40-OX40 ligand (OX40L) interaction in Th cell differentiation remains contentious. In vitro studies have revealed a Th2-biased effect by OX40 signals in T cells. However, in vivo studies demonstrated that OX40-OX40L interaction is involved in responses either Th1 or Th2, or both, which appears to be dependent on the experimental conditions used. We document in our report Th cell differentiation in OX40L-deficient and OX40L-transgenic (Tg) mice in response to protein antigens (Ag) and to Leishmania major (L. major) infection. Upon immunization with protein Ag, we demonstrate the adjuvant effect of OX40 signals during in vivo Th2 responses. However, adjuvant treatment to mice ameliorates the Th2-specific effect of OX40-OX40L interaction and rather induces concurrent promotion of both Th1 and Th2 responses via OX40 signals. Thus, previous reports showing promotion of Th1 response by OX40-OX40L interaction may in actual fact be affected by the adjuvant effects mediated by the various experimental conditions. Indeed, constitutive OX40-OX40L interactions in OX40L-Tg mice converted the normally resistant C57BL/6 strain, into a susceptible status following L. major infection due to an extraordinary elevated Th2 response. These results provide convincing evidence demonstrating that the OX40-OX40L interaction is paramount in the development of Th2 responses in vivo.

Animals↗

PubMed2006

Endocrine disruptors that deplete glutathione levels in APC promote Th2 polarization in mice leading to the exacerbation of airway inflammation.

Endocrine-disrupting chemicals (EDC) are ubiquitous in environment and may have various undesirable effects on human health. In the present study, we have shown that some EDC [benzophenone, p-octylphenol, and tributyltin chloride (TBT)] promoted strong Th2 polarization via suppression and augmentation of Th1 and Th2 development, respectively, from naive CD4+ T cells primed with anti-CD3 and splenic antigen-presenting cells (APC). The effect was indicated to be indirect via suppression of IL-12 production and augmentation of IL-10 production of APC, which are critical for the Th1 and Th2 development, respectively. Such modulation of cytokine production by EDC was associated with reduction of intracellular glutathione levels in APC. IL-10 deprivation or the addition of N-acetylcysteine, which replenishes intracellular glutathione level during priming, cancelled the effect of EDC on the promotion of Th2 polarization. Oral administration of TBT, which most effectively promoted Th2 polarization in vitro, exacerbated airway inflammation in a murine model of allergic asthma with concomitant enhancement of Th2-type immunity. Collectively these results suggest that EDC such as benzophenone, p-octylphenol, and TBT promote Th2 polarization indirectly via the depletion of glutathione in APC and subsequent modulation of IL-10 and IL-12 production that might result in the exacerbation of allergic diseases.

Animals↗

PubMed1999

Assessment of chemokine receptor expression by human Th1 and Th2 cells in vitro and in vivo.

The preferential association of some chemokine receptors with human Th1 or Th2 cells has recently been reported. In this study, the expression of CCR3, CCR5, CXCR3, and CXCR4 were analyzed by flow cytometry in three distinct in vitro models of Th1/Th2 polarization, activated naive and memory T cells, and T-cell clones, in which the intracellular synthesis of interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) and the surface expression of CD30 and LAG-3 were also assessed. Moreover, by using immunohistochemistry the in vivo expression of CCR3, CCR5, CXCR3, and CXCR4 was examined in the gut of patients suffering from Crohn's disease, a Th1-dominated disorder, and in the skin of patients suffering from systemic sclerosis, a Th2-dominated disorder. CCR5 and LAG-3 exhibited the same pathway of Th1 association, whereas CXCR3 did not discriminate between Th1- and Th2-dominated responses. On the other hand, CCR3 was found only occasionally in a small proportion of allergen-specific memory T cells with Th2/ThO profile of cytokine production in vitro. However, it was neither seen in Th2-polarized activated naive T cells nor in established Th2 clones and could be detected in vivo only on non-T cells. Finally, whereas CXCR4 expression was not limited to Th2 cells in vivo, it was markedly up-regulated by IL-4 and down-regulated by IFN-gamma in vitro. Thus, the results of this study confirm the existence of flexible programs of chemokine receptor expression during the development of Th1 and Th2 cells. However, caution is advised in interpreting these receptors as surrogate markers of a given type of effector response.

Clone Cells↗

PubMed1996

Reconstitution of germinal center formation in nude mice with Th1 and Th2 clones.

We investigated the ability of hemocyanin (KLH)-specific cloned CD4+ T cells expressing defined cytokine profiles to support germinal center (GC) formation in syngeneic athymic recipients in response to hapten-KLH challenge. Th1 clones producing IL-2 and IFN-gamma did not by themselves increase GC production above background, while Th2 cells producing IL-4 and IL-5 did. However, the combination of Th1 and Th2 cytokines was more effective than Th2 cytokines alone, suggesting a synergistic effect in this aspect of their help for B cells. In contrast to GC formation, antibody production could be induced with Th1 or Th2 clones given separately (Th1 clones inducing IgG2a, and Th2 clones inducing IgG1 and IgE). These results indicate that the T cell requirements for GC production are different from those for isotype switching and Ig secretion. It is postulated that the synergy between Th1 and Th2 cells in the induction of GC formation reflects the synergy between Th1 and Th2 cytokines, such as IFN-gamma and IL-5, in promotion of GC cell proliferation.

Adoptive Transfer↗

PubMed1995

Biology of human TH1 and TH2 cells.

Evidence is accumulating to suggest the existence of polarized human T-cell responses, reminiscent of TH1 and TH2 subsets described for mouse T cells. Human TH1 cells preferentially develop during infections by intracellular bacteria and trigger phagocyte-mediated host defense, whereas TH2 cells, which predominate during helminthic infestations and in response to common environmental allergens, are responsible for phagocyte-independent host response. Human TH1 and TH2 cells exhibit not only different functional properties but probably also distinct surface markers; TH2, but not TH1, clones express membrane CD30 and release the soluble form of CD30, a member of the TNF receptor superfamily. The cytokine profile of "natural immunity" evoked by different offending agents in the context of different host genetic backgrounds appears to be the most critical factor in determining the phenotype of the subsequent specific response. IL-12 and IFN-alpha and gamma produced by macrophages and NK cells favor the development of TH1 cells, whereas the early production of IL-4 by a still-unidentified cell type favors the development of TH2 cells. Clearly, polarized human TH1 and TH2 responses not only play different roles in protection, they can also promote different immunopathological reactions. Strong and persistent TH1 responses seen to be involved in organ-specific autoimmunity, contact dermatitis, and some chronic inflammatory disorders of unknown etiology. In contrast, polarized TH2 responses favor a reduced protection against the majority of infectious agents (including HIV) and, in genetically predisposed hosts, are responsible for triggering of allergic atopic disorders.

Humans↗

PubMed2006

Respiratory syncytial virus (RSV) evades the human adaptive immune system by skewing the Th1/Th2 cytokine balance toward increased levels of Th2 cytokines and IgE, markers of allergy--a review.

Infection of infants in their first year of life, children and elderly people with the respiratory syncytial virus (RSV) endangers the life of the patient. An attempt to develop a formalin-inactivated RSV (FI-RSV) vaccine during the 1960s resulted in an aggravated infection in immunized children, leading to hospitalization, while infection of non-immunized children produced much milder symptoms. The reason for this remained an enigma, one which was gradually solved over the last decade by many researchers who studied the molecular biology of RSV infection of respiratory ciliary cells. Clinical studies of RSV-infected patients indicated increased levels of Th2 cytokines and IgE in the patients' sera, suggesting that an allergy-like condition developed during infection. The biomarkers of allergy caused by endogenous or environmental allergens include a marked increase of the Th2 cytokine IL-4 and IgE non-neutralizing antibodies to the allergen. The way allergens trigger allergy was deciphered recently, and will be discussed later. Studies of RSV infection led to the suggestion that RSV patients suffer from allergy prior to RSV infection, a concept that was later abandoned. Studies on HIV-1 [Y. Becker, Virus Genes 28, 319-331 (2005)] research led me to the hypothesis that since HIV-1 infection induces a marked increase of IL-4 and IgE in serum, an allergy-like condition, the AIDS stage is the result of an allergen motif that is embedded in the shed viral gp120 molecules. It is hypothesized that the viral-soluble G glycoprotein (sG) contains a T cell superantigen (Tsag) that is capable of binding to the V(H)3 domain of IgE/FcepsilonRI(+) hematopoietic cells, basophils, mast cells and monocytes, similar to the case of allergens, and that this aggregation causes these innate system cells to degranulate and release large amounts of Th2 cytokines (IL-4, IL-5, IL-10, IL-13) into the blood. The way these Th2 cytokines skew the Th1/Th2 balance toward Th2 > Th1 will be discussed. The aim of the present review is to base RSV pathogenicity on the numerous very good analyses of the virus genes and to suggest a therapeutic approach to treatment that is directed at preventing the inhibitory effects of Th2 cytokines on the adaptive immune system of the patients, instead of inhibiting RSV replication by antivirals. The review of the molecular research on the role of the viral fusion (F) and attachment (G) glycoproteins of RSV provided information on their role in the virus infection: early in infection the F glycoprotein induces Th1 cells to release the Th1 cytokines IL-2, IL-12 and IFN-gamma to activate precursors CTLs (pCTLs) to become anti-RSV CTLs. The G and sG glycoproteins attach to FKNR1(+) ciliary respiratory epithelial cells as well as directly to eosinophils to the lungs. The sG T cell antigen can also induce the release of large amounts of Th2 cytokines from CD4(+) T cells and from FCepsilonRI(+) mast cells, basophils and monocytes. By comparison to HIV-1 gp120 it is possible to show that in the G and sG proteins the T cell antigen resembles the CD4(+) T cell superantigen (=allergen) domain of HIV-1 gp120 which aggregates with IgE/FCepsilonRI(+) hematopoietic cells. The increased IL-4 level in the serum inhibits the adaptive immune response: IL-4Ralpha(+) Th1 cells stop Th1 cytokine synthesis and IL-4Ralpha(+) B cells stop the synthesis of antiviral IgG and IgA and switch to IgE synthesis. In addition, the hematopoietic cells release histamine and prostaglandin which induce wheezing. The gradual increase of sG molecules creates a gradient of fractalkine (FKN) which directs IL-5-activated eosinophils to the lungs of the patient.

Animals↗

PubMed2004

Endogenous IL-4 and IFN-gamma are essential for expression of Th2, but not Th1 cytokine message during the early differentiation of human CD4+ T helper cells.

CD4+ T cells can be divided into several distinct effector subpopulations, including Th1 and Th2. Human Th1 cells are essential for the establishment of cellular immune responses, whereas Th2 cells for immunoglobulin E synthesize by B cells and immunoregulation. This study determines the involvement of exogenously and endogenously produced T cell-derived cytokines during early differentiation of naive CD4+ T cells into Th1 and Th2 cells. Cytokine gene expression of purified experienced and naive CD4+T cells in the presence or absence of Th-directing cytokines and neutralizing anti-cytokine antibodies, was determined at early (20 and 40 h) time points, after in vitro activation. These studies demonstrated that: (1) endogenously produced, T cell-derived cytokines (interferon [IFN]-gamma and interleukin [IL]-4), play an important role in the regulation of early gene expression of Th2, but not Th1 type cytokines; (2) Th1-related cytokines, IFN-gamma, and IL-2, are preferentially expressed in cultures directed toward Th1, as compared with Th2; and (3) IL-4 and IFN-gamma showed early message expression in both differentiating populations, indicating a mixed profile of Th1 and Th2 cytokine production in early human Th cell development. These findings point to the critical role for endogenously produced cytokines in the early differentiation of human Th1 or Th2 cells.

Cell Differentiation↗