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PubMed1991

Membranes from both Th1 and Th2 T cell clones stimulate B cell proliferation and prepare B cells for lymphokine-induced differentiation to secrete Ig.

Plasma membranes from the mitogen-activated mouse Th2 cell clone D10.G4.1 have recently been shown to provide the cell contact-dependent signals necessary for the induction of small B cell proliferation. Together with the Th2-derived lymphokines IL-4 and IL-5, these membranes stimulate production of Ig isotypes identical to those produced when B cells were stimulated by intact Th2 cells. In contrast, Th1 clones are poor inducers of Ig production in vitro. This could be solely due to differences in the lymphokines released by Th1 and Th2 cells or to differences in the cell-cell contact signals delivered by activated Th1 and Th2 cells. We report that membranes from three different activated Th1 clones induced strong Ag-independent proliferation of small dense B cells. The level of B cell proliferation was enhanced approximately fourfold by the addition of lymphokine-containing supernatant from Con A-activated Th2 cells and was unaffected by any of the lymphokine-containing supernatants from Con A-activated Th1 clones. As with D10.G4.1 membranes, Th1 membranes alone induced B cell proliferation but not secretion of Ig. However, addition of supernatant from Con A-activated D10.G41 cells, but not any supernatants from Con A-activated Th1 cells, induced Ig secretion of all isotypes. These effects were shown to not simply result from increased B cell numbers after stimulation with Th2 lymphokines. Thus, Th1 cell clones seem to poorly induce antibody responses entirely because of their lymphokine repertoire and not because of differences or deficiencies in the ability of these cells to deliver cell contact-dependent signals to B cells.

Animals↗
PubMed1990

Heterogeneity of helper/inducer T lymphocytes. III. Responses of IL-2- and IL-4-producing (Th1 and Th2) clones to antigens presented by different accessory cells.

Murine CD4+ T cell clones have been classified into at least two subsets, Th1 and Th2, on the basis of their distinct lymphokine secretion profiles and functions. In the present study, we compared the functional responses of Th1 and Th2 clones to Ag presentation by splenic B cells and peritoneal macrophages. Th2 clones secreted IL-4 in response to Ag presented by resting B cells, but their optimal proliferation required the addition of IL-1 or a source of IL-1. The degree of IL-1 dependence varied among the four Th2 clones examined. In contrast, Th1 clones secreted IL-2 and proliferated in response to Ag presented by both B cells and macrophages, without any requirement for exogenous IL-1. Furthermore, the proliferation of Th2 clones in response to Ag presented by splenocytes or macrophages was inhibited by an IL-1R antagonist. These results indicate that IL-1 is an important costimulator for the expansion of the Th2 subset of CD4+ T cells. The different requirements for the proliferation of Th1 and Th2 cells may be responsible for the preferential expansion of one or the other subset under different conditions of immunization.

Animals↗
PubMed1990

Evidence implicating utilization of different T cell receptor-associated signaling pathways by TH1 and TH2 clones.

We have reported recently that high concentrations of anti-CD3 mAb inhibited IL-2-dependent proliferation of TH1 but not TH2 clones. The selective inhibitory effect on TH1 clones suggested that the two helper T lymphocyte subsets might utilize different TCR-associated signal transduction mechanisms. In the present study, we demonstrate that this distinction was not due to a gross difference in the level of TCR expression by TH1 and TH2 clones. Inhibition of TH1 proliferation by anti-CD3 mAb appeared to depend on calcium for maximal effect, suggesting that a substantial elevation of intracellular free calcium concentration ([Ca2+]i) might not occur after ligation of the TCR complex of TH2 clones. Calcium ionophore inhibited IL-2-dependent proliferation of both subsets, suggesting that receptor/ligand systems which stimulate elevated [Ca2+]i would be expected to inhibit proliferation. Although elevated [Ca2+]i and generation of inositol phosphates were readily detected in TH1 clones, these second messengers were not detected following stimulation of TH2 clones via the TCR complex. In addition, lymphokine production by TH1 clones was more sensitive to inhibition by cholera toxin, 8-bromoadenosine 3':5'-cyclic monophosphate, and cyclosporin A than was lymphokine production by TH2 clones. Collectively, these results suggest that TH1 and TH2 clones utilize distinct TCR-associated signal transduction mechanisms for lymphokine gene expression. The difference in signaling mechanisms suggests a potential pharmacologic target for intervention in situations where inappropriate activation of TH1 or TH2 cells occurs in vivo.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1994

Cells of Th2 cytokine phenotype prevent LPS-induced lethality during murine graft-versus-host reaction. Regulation of cytokines and CD8+ lymphoid engraftment.

A murine parent-into-F1 graft-vs-host reaction (GVHR) model that utilizes LPS to induce lethality was used to evaluate the in vivo regulatory role of donor cells of Th2 cytokine phenotype. Transfer of B6 spleen cells into B6C3F1 hosts was lethal when LPS endotoxin (15 micrograms) was administered on day 7 after cell transfer. Parental cells of Th2 cytokine phenotype were generated by treating B6 mice in vivo with a combination of IL-2 and IL-4 or with high dose IL-2. The CD4-enriched population from these cytokine-treated mice expressed and secreted increased levels of IL-4 and IL-10, with concomitantly decreased IL-2 and IFN-gamma. Cell mixing experiments (parental spleen cells+parental CD4-enriched. Th2-type cells) demonstrated that the Th2-type cells protected F1 hosts from LPS-induced lethality. These mice were analyzed to study possible mechanisms by which this protection was mediated. Compared with mice undergoing LPS-induced lethality during GVHR, Th2-protected mice had: 1) lower levels of donor CD8+ lymphoid engraftment, 2) in vivo suppression of IFN-gamma mRNA, 3) in vivo augmentation of IL-4 mRNA, and 4) a reduction in serum TNF-alpha. We thus conclude that donor cells of Th2 cytokine phenotype prevent LPS-induced, TNF-alpha-mediated lethality during GVHR, and that this protection is associated with regulation of both cellular- and cytokine-mediated events. As a result, we propose that cells of Th2 cytokine phenotype may represent a novel approach for establishing allogeneic lymphoid engraftment without lethal graft-vs-host disease.

Animals↗
PubMed1993

Exacerbation of murine herpes simplex virus-mediated stromal keratitis by Th2 type T cells.

Corneal infection of susceptible mice with HSV-1 causes herpetic stromal keratitis (HSK), which serves as a model of human HSK. To study the properties of the T lymphocytes involved in HSK, susceptible mice were immunized with the synthetic peptide corresponding to the amino terminal of HSV-1-associated glycoprotein D (gD 5-23). A CD4+ long-term T cell line and a clone bearing V beta 8.2 TCR were derived from peptide-primed lymph node cells. These T cells recognize gD 5-23 peptide in the context of I-Ed and require CD4 and LFA-1 for Ag-specific proliferation. Significantly, a truncated peptide gD 15-23 induced vigorous proliferation, indicating that these 9 amino acids constitute an epitope recognized by these T cells. The gD-specific T cells produced IL-4 and used it as the autocrine growth factor and hence belong to the Th2 subtype. Adoptive transfer of gD-specific Th2 cells into susceptible mice increased both the onset and severity of HSK after corneal HSV-1 infection. Injection of gD-specific Th2 cells without HSV-1 infection failed to cause eye damage. In addition, an irrelevant Ag-specific Th2 clone failed to induce similar tissue damage when the corresponding Ag was applied to the eye. These data indicate that the T cell-mediated exacerbation of HSK in these studies is dependent on the specific recognition of gD after corneal HSV-1 infection. Finally, gD-specific Th2 cell transfer also rendered HSK-resistant mice susceptible for HSK, suggesting that the freedom from HSK in resistant mice may primarily be due to their inability to produce the pathogenic Th2 cells. The data collectively implicate an important role for Th2 cells in the induction of HSV-mediated keratitis in mice.

Amino Acid Sequence↗
PubMed1993

Evolving T cell responses in murine schistosomiasis. Th2 cells mediate secondary granulomatous hypersensitivity and are regulated by CD8+ T cells in vivo.

The dynamics of T cell maturation and regulation were examined during the granulomatous response to Schistosoma mansoni eggs under conditions of primary (PRIM), secondary vigorous (VIG), and secondary immunomodulated (MOD) immunity. The patterns of VIG and MOD GR (GR) formation were established in naive CBA mice by transfer of lymphoid cells from S. mansoni-infected donors at the VIG and MOD stages of infection. Sequential production of IFN, IL-2, and IL-4 was assessed at the GR and in draining lymph nodes (LN) to determine the participation of Th1 (IFN-producing) and Th2 (IL-4/IL-5-producing) cells. The PRIM GR produced IFN in the growth phase (2-16 days) and IL-4 was detected only after lesions were established (16-24 days). The PRIM LN showed coincident production of IFN, IL-2, and IL-4 on day 4 followed by mainly IL-4 and IL-2 production on day 8, consistent with Th2 differentiation via a Th0 precursor. The VIG GR produced high levels of IL-4 in the growth phase (4-8 days) although IFN remained at modest levels. The VIG LN showed increased cytokine levels consistent with an anamnestic response and again the pattern suggested Th2 differentiation from Th0 cells. The MOD mice had abrogated GR IL-4 levels and arrested Th2 differentiation in LN. In vitro mix studies indicated that the impaired cytokine production was not due to direct suppression. The role of Ts cells was next explored by T cell subset depletion. Pan-T cell depletion of VIG cells profoundly abrogated IL-4 production although CD8+ cell depletion augmented GR area by 70% as well as local and regional IL-4 production by 100 to 150%. Similarly, CD8+ cell depletion of MOD cells augmented GR size and IL-4 production but the response was less than corresponding VIG mice, suggesting that Th activity was reduced in MOD mice. Transfer studies indicated that CD8+ cells inhibited Th2 maturation in LN. Thus, the schistosome egg GR demonstrated a Th1-like pattern in the PRIM response followed by a Th2 pattern in the VIG stage and abrogated Th2 activity in the MOD stage. Finally, the phenomenon of "spontaneous modulation" likely represents the cumulative action of CD8+ cells which steadily erode the Th population.

Animals↗
PubMed1998

NF-kappaB in Th2 cells: delayed and long-lasting induction through the TCR complex.

Nucelar NFkappaB was analyzed in murine Th2 cells after stimulation via the TCR pathway. Signals delivered through the TCR/CD3 complex induced active NFkappaB translocation to the nucleus of Th2 cells after a late phase (24 h) of the activation process, which is in contrast to the rapid appearance of nuclear NFkappaB (3 h) in Th1 cells after the same stimulation. The slow kinetic of NFkappaB nuclear uptake in Th2 cells was not accelerated by CD28 triggering or under stimulation with antigen plus antigen-presenting cells. Th1 and Th2 cells were also different in the composition of NFkappaB complexes induced. Whereas in Th1 cells TCR triggering induced the presence of nuclear p50.p65 heterodimers, in Th2 cells the complexes induced were shown to be composed of p65 plus another NFkappaB protein distinct from p50. The delayed NFkappaB induction in Th2 cells was dependent on protein synthesis and the significance of this is discussed.

Animals↗
PubMed2000

Site of antigen delivery can influence T cell priming: pulmonary environment promotes preferential Th2-type differentiation.

Delivery of foreign antigens to mucosal surfaces, such as the pulmonary airways, has been shown to preferentially induce Th2-mediated responses in humans and in mice. What is not clear from these studies is whether this preferential skewing in responses is the result of the limited types of antigen being administered and/or a bias towards using particular genetic strains of mice, or whether the lung environment in itself provides a favored site for the priming of Th2-type cells. We have addressed this issue using an antigen/mouse strain combination that, under typical conditions of immunization, is strongly biased towards priming for Th1 CD4+ T cells. We show that Leishmania major parasites delivered to C57BL/6 mice via an intranasal route fail to induce the expected Th1-dominated responses and instead preferentially prime for Th2 responses. These included an influx in lymphocytes and eosinophils into alveoli, as well as the induction of Th2-type foci of inflammation around pulmonary blood vessels and airways. Moreover, high levels of Th2-associated cytokines (IL-4 and IL-5) were generated when lung-draining lymph node and tissue cells were restimulated with L. major lysate. These data suggest that the lung environment per se favors Th differentiation towards the Th2 phenotype.

Administration, Intranasal↗
PubMed2002

Th2-type granuloma development in acute murine schistosomiasis is only partly dependent on CD4+ T cells as the source of IL-4.

Schistosome granulomas produce IL-4, important for Th2 granuloma expression. We defined the origins of IL-4 within these granulomas and the role of IL-4-producing CD4(+) T cells in Th2 granuloma development. Dispersed granuloma cells spontaneously produced IL-4 independently of T cells, whereas IL-5 production was T cell dependent. Granuloma IL-4 mRNA localized to the non-T cells and IL-5 to T cells. Granuloma CD4(+) T and NK cells, but not B cells produced IL-4 and IL-5 in vitro. B cell-/- mice generated Th2 granulomas that produced IL-4 and IL-5 normally. Granuloma eosinophils expressed no IL-4 or IL-5 mRNA. Granulomas in WWv mast cell-deficient mice lacked mast cells. The dispersed granuloma cells from WWv mice released IL-4 only after T cell stimulation, suggesting that mast cells influenced the constitutive component of IL-4 production. Rag-1 animals (T/B/NK T cell deficient) given schistosomiasis after reconstitution with splenocytes from naive mice produced Th2 granulomas. Mice reconstituted to create selective CD4(+) T cell IL-4 knockout animals developed eosinophilic granulomas that made IL-4. Thus, granulomas contain several cell types that produce IL-4. Mast cells are not needed to form Th2 granulomas, but influence IL-4 release. Th2 granuloma development in schistosomiasis is only partly dependent on IL-4-producing CD4(+) T cells.

Animals↗
PubMed2002

Targeting CLA/E-selectin interactions prevents CCR4-mediated recruitment of human Th2 memory cells to human skin in vivo.

Naive Th cells, bearing receptors for cutaneous antigens, become activated in skin-draining lymph nodes and express cutaneous lymphocyte antigen (CLA), which confers to these cells the capacity to migrate into the skin to exert their normal effector functions. In the case of atopic dermatitis (AD), allergen-specific Th2 cells generate exacerbated responses and induce skin inflammation. In such a situation, interfering with the specific mechanism of skin homing would provide a therapeutic benefit. Here we report that CLA+ Th2 memory cells, derived from skin lesions of AD patients, selectively migrate to human skin grafts transplanted onto SCID mice in response to CCR4 but not CCR3, CCR8 or CXCR3 ligands. Skin homing of human CCR4+ Th2 memory cells was Pertussis toxin sensitive and restricted to the CLA+ subset. Furthermore, treatment of these mice with anti-E-selectin monoclonal antibody was sufficient to prevent CCL22-mediated Th2 cell migration to human skin, which both, validates the model and highlights the importance of CLA/E-selectin interactions in the homing process of Th2 cells to the skin. Using this mechanistic model we demonstrate that skin homing of human Th2 memory cells can be efficiently suppressed using a low molecular weight E-selectin antagonist, which is of clinical relevance for the treatment of inflammatory skin diseases, including AD.

Adult↗
PubMed1997

Th1 and Th2 subsets equally undergo Fas-dependent and -independent activation-induced cell death.

Stimulation of previously activated T cells results in apoptosis, termed activation-induced cell death (AICD). Recent analysis revealed that the Fas/Fas ligand (FasL) interaction is predominantly involved in AICD of T cells. Furthermore, based on the analysis of various T cell clones and lines, it has been reported that FasL is expressed mainly in Th1 but not in Th2 cells. However, the exact expression pattern of FasL and its function in normal activated T cells has not been determined. In the present study, by utilizing completely differentiated Th1 and Th2 cell populations obtained from ovalbumin-specific T cell receptor (TCR)-transgenic mice, the FasL expression on Th1 and Th2 was determined. Furthermore, involvement of Fas-FasL interaction in AICD of Th1 and Th2 cells was analyzed by two approaches: one was the inhibition of AICD by anti-FasL monoclonal antibodies, and the other AICD of Th1/Th2 subsets from TCR-transgenic mice backcrossed to lpr mice. We demonstrated that Th2 cells express FasL on the cell surface at a level similar to that expressed by Th1 cells, and that both subsets were equally susceptible to the Fas-mediated AICD. These observations suggest not only that the expression of FasL is not always correlated with Th subsets as defined by the cytokine-producing profile, but also that the responses of both Th1 and Th2 subsets are regulated by Fas-mediated AICD. Finally, analysis of the kinetics of AICD revealed a novel Fas/FasL-independent pathway in its initial stage. These findings revealed the precise function of Fas/FasL-mediated as well as Fas/FasL-independent AICD in the regulation of helper T cell responses.

Animals↗
PubMed1997

Deviation of pancreas-infiltrating cells to Th2 by interleukin-12 antagonist administration inhibits autoimmune diabetes.

Nonobese diabetic (NOD) mice develop spontaneous insulin-dependent diabetes mellitus (IDDM), and the pancreas-infiltrating T cells invariably show a Th1 phenotype. We demonstrated here that the interleukin (IL)-12 antagonist (p40)2 can deviate the default Th1 development of naive T cell receptor (TCR)-transgenic CD4+ cells to the Th2 pathway in vitro. Although (p40)2 does not modify the cytokine profile of polarized Th1 cells, it prevents further recruitment of CD4- cells into the Th1 subset. To study the involvement of Th1 and Th2 cells in the initiation and progression of IDDM, we targeted endogenous IL-12 by administration of (p40)2 in NOD mice. (p40)2 administration to NOD mice inhibits interferon-gamma but not IL-10 production in response to lipopolysaccharide (LPS) or to the putative autoantigen IA-2. Serum immunoglobulin isotypes determined after (p40)2 treatment indicate an increase in Th2 and a decrease in Th1 helper activity. Administration of (p40)2 from 3 weeks of age onwards, before the onset of insulitis, results in the deviation of pancreas-infiltrating CD4+ but not CD8+ cells to the Th2 phenotype as well as in the reduction of spontaneous and cyclophosphamide-accelerated IDDM. After treating NOD mice with (p40)2 from 9 weeks of age, when insulitis is well established, few Th2 and a reduced percentage of Th1 cells are found in the pancreas. This is associated with a slightly decreased incidence of spontaneous IDDM, but no protection from cyclophosphamide-accelerated IDDM. In conclusion, deviation of pancreas-infiltrating CD4+ cells to Th2 is associated with protection from IDDM. However, targeting IL-12 after the onset of insulitis, when the pancreas contains polarized Th1 cells, is not sufficient to induce an effective immune deviation able to significantly modify the course of disease.

Animals↗
PubMed2003

Critical role for OX40 ligand in the development of pathogenic Th2 cells in a murine model of asthma.

Bronchial asthma is characterized by massive infiltration of eosinophils and airway hyperreactivity (AHR), which are caused by overproduction of Th2 cytokines (IL-4, IL-5, and IL-13) by allergen-specific T cells. We recently demonstrated a critical contribution of OX40 ligand (OX40L) to the development of Th2-mediated experimental leishmaniasis. In this study, we have examined the role of OX40L in the development of Th2-mediated pulmonary inflammation by utilizing OX40L-deficient mice and a neutralizing anti-OX40L mAb in a murine model of asthma. Sensitization and airway challenge with ovalbumin in wild-type BALB/c mice induced a typical allergic asthma characterized by AHR, accumulation of eosinophils, increased mucus production, and high levels of Th2 cytokines in the lung. All these asthmatic responses were not induced in OX40L-deficient BALB/c mice. Administration of neutralizing anti-OX40L mAb in wild-type BALB/c mice during the sensitization period also abolished the induction of asthmatic responses. In contrast, administration of anti-OX40L mAb during the challenge period did not inhibit the asthmatic responses. These results indicate a critical role for OX40L in the induction phase, which leads to the development of pathogenic Th2 cells, but not in the effector phase, which includes migration and activation of pathogenic Th2 cells in the lung.

Animals↗
PubMed2003

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

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

Animals↗
PubMed2004

Environmental pollutant tributyltin promotes Th2 polarization and exacerbates airway inflammation.

It has been shown that a relatively high dose of tributyltin (TBT), which is recognized as a particularly notable environmental pollutant, exerts immunotoxic effects such as thymic atrophy via induction of T cell apoptosis. However, the effect of low doses of TBT on the immune responses remains unknown. Here we show that environmentally relevant doses of 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). TBT-induced Th2 polarization was indirect, working through APC via suppression of IL-12 production by macrophages/DC and the augmentation of IL-10 production by B cells. Th2 polarization was also induced in mice treated with TBT and immunized with OVA or infected with Nippostrongylus brasiliensis. Furthermore, airway inflammation in mice sensitized and challenged with OVA was exacerbated by the administration of TBT with concomitant augmentation of Th2-type immunity. Our results highlight the fact that an important environmental pollutant TBT may present significant risk for the induction of allergic diseases via promotion of Th2 polarization.

Animals↗
PubMed2003

Differential effects of Th1 and Th2 lymphocyte supernatants on human microglia.

We assessed the effects of soluble molecules (supernatants) produced by pro- (Th1) and anti- (Th2) inflammatory T-cell lines on the capacity of adult human CNS-derived microglia to express or produce selected cell surface and soluble molecules that regulate immune reactivity or impact on tissue protection/repair within the CNS. Treatment of microglia with supernatants from allo-antigen and myelin basic protein-specific Th1 cell lines augmented expression of cell surface molecules MHC class II, CD80, CD86, CD40, and CD54, enhanced the functional antigen-presenting cell capacity of microglia in a mixed lymphocyte reaction, and increased cytokine/chemokine secretion (TNFalpha, IL-6, and CXCL10/IP-10). These Th1-induced effects were not reproduced by interferon-gamma (IFNgamma) alone and were only incompletely blocked by anti-IFNgamma antibody. Th2 cell supernatant treatments did not alter costimulatory/adhesion molecule expression or induce cytokine/chemokine production by microglia. Th2 treatment, furthermore, failed to reduce the induction observed in response to Th1 supernatants. Neither Th1 nor Th2 supernatants induced production of the neurotrophin molecules, nerve growth factor, or brain-derived neurotrophic factor. Our results suggest that soluble molecules released by Th1 and not Th2 cells that infiltrate the CNS can stimulate resident microglia to acquire enhanced effector and accessory cell functions; the Th1-induced effects were not downregulated by Th2 supernatant-mediated bystander suppression.

Cell-Free System↗
PubMed1995

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

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

Animals↗
PubMed1998

Differential expression of alpha3 fucosyltransferases in Th1 and Th2 cells correlates with their ability to bind P-selectin.

One of the key control points in the trafficking of the T cell effector subsets, Th1 and Th2, to sites of inflammation is their migration out of the bloodstream. The mechanism by which the cells initially adhere to the endothelium is dependent on the selectin family of adhesion molecules. Only polarised Th1 cells are capable of binding P-selectin despite both Th1 and Th2 cells expressing PSGL-1, the P-selectin ligand. This may be due to a secondary modification of PSGL-1 that is present on Th1 but not Th2 cells. One key modification of PSGL-1 is the alpha3 fucosylation of the O-glycans. To address whether the binding of Th1 and Th2 cells may be regulated by fucosylation, we have studied the expression of the alpha3 fucosyltransferases, FucT-IV and VII, using in vitro differentiated mouse T cells. Messenger RNA levels for both FucT-IV and VII were found to be higher in Th1 than Th2 cells. alpha3 fucosyltransferase enzyme activities were also elevated in Th1 cells. The increased expression of the alpha3 fucosyltransferases in Th1 cells correlated with the ability of Th1, but not Th2, cells to bind to P-selectin. Thus, the regulation of the binding of effector T cells to the endothelium, and subsequent trafficking to inflammatory sites, may be controlled by the fucosylation state of PSGL-1 mediated by the selective expression of the alpha3 fucosyltransferases.

Amino Acid Sequence↗