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At least 37 records · Page 2Linked to original sources
PubMed2004

Protein kinase C theta is critical for the development of in vivo T helper (Th)2 cell but not Th1 cell responses.

The serine/threonine-specific protein kinase C (PKC)-theta is predominantly expressed in T cells and localizes to the center of the immunological synapse upon T cell receptor (TCR) and CD28 signaling. T cells deficient in PKC-theta exhibit reduced interleukin (IL)-2 production and proliferative responses in vitro, however, its significance in vivo remains unclear. We found that pkc-theta(-/-) mice were protected from pulmonary allergic hypersensitivity responses such as airway hyperresponsiveness, eosinophilia, and immunoglobulin E production to inhaled allergen. Furthermore, T helper (Th)2 cell immune responses against Nippostrongylus brasiliensis were severely impaired in pkc-theta(-/-) mice. In striking contrast, pkc-theta(-/-) mice on both the C57BL/6 background and the normally susceptible BALB/c background mounted protective Th1 immune responses and were resistant against infection with Leishmania major. Using in vitro TCR transgenic T cell-dendritic cell coculture systems and antigen concentration-dependent Th polarization, PKC-theta-deficient T cells were found to differentiate into Th1 cells after activation with high concentrations of specific peptide, but to have compromised Th2 development at low antigen concentration. The addition of IL-2 partially reconstituted Th2 development in pkc-theta(-/-) T cells, consistent with an important role for this cytokine in Th2 polarization. Taken together, our results reveal a central role for PKC-theta signaling during Th2 responses.

Animals↗
PubMedDate not supplied

Anti-allergic Psidium guajava extracts exert an antitumor effect by inhibition of T regulatory cells and resultant augmentation of Th1 cells.

Th1 polarization is one of the mechanisms underlying the therapeutic effects of herbal medicine. The action of anti-allergic agents from Psidium guajava (P. guajava) on T cell immunity in mice was investigated. The addition of P. guajava extracts blocked IL-10-mediated, in vitro induction of T regulatory (Tr) cells from CD4+ splenocytes of C57BL/6 mice, whereas the extracts exerted only a weak or no effect on the development of Th1 and Th2 cells. Accordingly, Tr cells were not induced from splenocytes of mice administered orally with the extracts. Furthermore, P. guajava extracts shifted the Th1/Th2 balance to a Th1 dominant status by directly attenuating Tr cell activity. In a study of tumor immunity, mice pretreated with the extracts exhibited retarded growth of s.c. inoculated B16 melanoma cells. These findings suggest that P. guajava extracts are efficacious for the prevention of tumor development by depressing Tr cells and subsequently shifting to Th1 cells.

Animals↗
PubMed1997

Inhibition of IL-2 production by nitric oxide: a novel self-regulatory mechanism for Th1 cell proliferation.

Cloned Th1 cells, but not Th2 cells, specific for malaria antigen, produce nitric oxide (NO) when activated with specific antigen or Con A. Furthermore, NO inhibits proliferation of, and production of IL-2 and IFN-gamma by, Th1 but not Th2 cells. Here, it is demonstrated that the inhibition of Th1 cell proliferation by the NO donor S-nitroso-N-acetyl penicillamine (SNAP) can be reversed by the addition of rIL-2 but not of rIFN-gamma, suggesting that the inhibition of Th1 cells by NO may be preventing the production of IL-2. Dose-response studies showed that Th1 cells produce optimal levels of IL-2 and a proliferative response, and no detectable NO, when stimulated with relatively low concentrations of antigen or mitogen in vitro. As the antigen/mitogen increased, however, high levels of NO were produced, accompanied by a concomitant reduction in IL-2 secretion and T cell proliferation. The proliferation of, and IL-2-IFN-gamma production by, naive CD4+ T cells from normal spleens activated with Con A in vitro can be similarly inhibited by SNAP. These results suggest that NO may serve as a self-regulatory molecule preventing the over-expansion of Th1 cells. Unrestricted Th1 cell activity has been implicated in a range of immunopathologies and autoimmune diseases. The proposed mechanism for down-regulation of Th1 cell function may also account for the suppression of lymphocyte proliferation observed in malaria infections.

Animals↗
PubMed2003

Delivery of antigen in allogeneic cells preferentially generates CD(4+) Th1 cells.

We have examined the possibility of evoking antigen-specific T cell immune response by using allogeneic cells as a source of adjuvant and also as a vehicle to deliver antigen. The mice were immunized with different preparations of antigen-pulsed allogeneic and syngeneic splenocytes. It was observed during the study that the animals immunized with antigen-pulsed mitomycin C treated allogeneic cells elicited antigen specific CD(4+) Th1 cell response. Predominant release of IL-2, interferon (IFN)-gamma and IgG2a-isotype also occurred. In contrast, mice immunized with antigen-pulsed syngeneic cells chiefly enhanced the production of interleukin (IL)-4 and IgG1-isotype. Further, allogeneic macrophages induced better T cell response than B cells or splenocytes and prominently induced the expression of B7-1 and B7-2. Immunization with antigen-pulsed macrophages provided better recall responses compared to B cells. This was manifested by the high LFA-1alpha and low CD45RB expression on T cells. Because it is already known that mitomycin C-treated cells undergo apoptosis and dendritic cells engulf apoptotic cells, we therefore propose that generation of T cell response using antigen-pulsed allogeneic cells may be due to the engulfment of these cells by dendritic cells, which may then process and present antigen entrapped in allogeneic cells to activate naive CD(4+) T cells and differentiate them to Th1 cells. This study therefore provides a rational basis for manipulating antigen-specific responses by immunizing with antigen-pulsed allogeneic cells.

Animals↗
PubMed1991

IL-10 acts on the antigen-presenting cell to inhibit cytokine production by Th1 cells.

Murine IL-10 (cytokine synthesis inhibitory factor) inhibits cytokine production by Th1 cell clones when they are activated under conditions requiring the presence of APC. By preincubating APC with IL-10, we demonstrate that IL-10 acts principally on APC to inhibit IFN-gamma production by Th1 clones. Moreover, IL-10 is not active when Th1 cells are stimulated with glutaraldehyde-fixed APC, which also indicates that its action involves regulation of APC function. Furthermore, IL-10 inhibits cytokine synthesis by Th1 cells stimulated with the super-antigen Staphylococcus enterotoxin B, which does not appear to require processing. Flow microfluorimetry purified splenic or peritoneal B cells and macrophages, and B cell and macrophage cell lines can present Ag to Th1 clones. However, IL-10 acts only on sorted macrophages and the macrophage cell line to suppress IFN-gamma production by Th1 clones. IL-10 does not show this effect when B cells are used as APC. In contrast, IL-10 does not impair the ability of APC to stimulate cytokine production by Th2 cells. IL-10 does not decrease IFN-gamma-induced I-Ad levels on a macrophage cell line. Inasmuch as IL-10 also inhibits IL-2-induced IFN-gamma production by Th1 cells in an Ag-free system requiring only the presence of accessory cells, these data suggest that IL-10 may inhibit macrophage accessory cell function which is independent of TCR-class II MHC interactions.

Animals↗
PubMed2002

Interleukin 21 is a T helper (Th) cell 2 cytokine that specifically inhibits the differentiation of naive Th cells into interferon gamma-producing Th1 cells.

The cytokine potential of developing T helper (Th) cells is directly shaped both positively and negatively by the cytokines expressed by the effector Th cell subsets. Here we find that the recently identified cytokine, interleukin (IL)-21, is preferentially expressed by Th2 cells when compared with Th1 cells generated in vitro and in vivo. Exposure of naive Th precursors to IL-21 inhibits interferon (IFN)-gamma production from developing Th1 cells. The repression of IFN-gamma production is specific in that the expression of other Th1 and Th2 cytokines is unaffected. IL-21 decreases the IL-12 responsiveness of developing Th cells by specifically reducing both signal transducer and activator of transcription 4 protein and mRNA expression. These results suggest that Th2 cell-derived IL-21 regulates the development of IFN-gamma-producing Th1 cells which could serve to amplify a Th2 response.

Animals↗
PubMed2003

Homing to nonlymphoid tissues is not necessary for effector Th1 cell differentiation.

The differentiation of naive T cells into effector Th1 cells is a complex process that may proceed in two steps, commitment and development. Initial TCR engagement and IFN-gamma signaling instruct the T cells to commit to the Th1 lineage, while subsequent IL-12 and potentially TCR signaling induces final differentiation into irreversible, Th1 effector cells. In agreement with a multistep process of Th1 cell differentiation, effector Th1 cell generation requires repeated TCR and cytokine signaling, thus raising the possibility that commitment and differentiation processes may occur in two distinct anatomical sites, the lymphoid organ and the site of infection, respectively. We tested this possibility using a model of skin sensitization that permits a direct analysis of Ag-specific T cells both within lymphoid organs and at the site of sensitization. We show in this study that Ag presentation in the skin does not induce further differentiation of skin-infiltrating T cells that are highly divided and fully differentiated effector cells. Thus, effector Th1 cell differentiation is completed within lymphoid organs. In addition, we examined the heterogeneity of CD4 T cell responses in vivo through the analysis of the expression, by activated T cells, of different selectins, including P-selectin ligand and CD62L known to define separable effector populations. We delineated, in lymph nodes, at least five distinct subpopulations of activated CD4 T cells with different phenotypes and recirculation properties. Collectively, these results show that the lymphoid environment orchestrates T cell activation to generate a repertoire of effector T cells with a diversity of effector functions.

Animals↗
PubMed2005

Rolling of Th1 cells via P-selectin glycoprotein ligand-1 stimulates LFA-1-mediated cell binding to ICAM-1.

Activated T cells migrate from the blood into nonlymphoid tissues through a multistep process that involves cell rolling, arrest, and transmigration. P-Selectin glycoprotein ligand-1 (PSGL-1) is a major ligand for P-selectin expressed on subsets of activated T cells such as Th1 cells and mediates cell rolling on vascular endothelium. Rolling cells are arrested through a firm adhesion step mediated by integrins. Although chemokines presented on the endothelium trigger integrin activation, a second mechanism has been proposed where signaling via rolling receptors directly activates integrins. In this study, we show that Ab-mediated cross-linking of the PSGL-1 on Th1 cells enhances LFA-1-dependent cell binding to ICAM-1. PSGL-1 cross-linking did not enhance soluble ICAM-1 binding but induced clustering of LFA-1 on the cell surface, suggesting that an increase in LFA-1 avidity may account for the enhanced binding to ICAM-1. Combined stimulation by PSGL-1 cross-linking and the Th1-stimulating chemokine CXCL10 or CCL5 showed a more than additive effect on LFA-1-mediated Th1 cell adhesion as well as on LFA-1 redistribution on the cell surface. Moreover, PSGL-1-mediated rolling on P-selectin enhanced the Th1 cell accumulation on ICAM-1 under flow conditions. PSGL-1 cross-linking induced activation of protein kinase C isoforms, and the increased Th1 cell adhesion observed under flow and also static conditions was strongly inhibited by calphostin C, implicating protein kinase C in the intracellular signaling in PSGL-1-mediated LFA-1 activation. These results support the idea that PSGL-1-mediated rolling interactions induce intracellular signals leading to integrin activation, facilitating Th1 cell arrest and subsequent migration into target tissues.

Animals↗
PubMed1999

Expression of L-selectin on Th1 cells is regulated by IL-12.

L-selectin has become established as a key molecule in the recirculation of naïve T cells from the blood to peripheral lymph nodes, yet little is known about its role in the migration of effector or memory cells. While differentiating naïve CD4+ T cells into Th1 and Th2 subsets in vitro, it was noted that L-selectin levels were maintained on the Th1 subset of cells. The expression of L-selectin on the Th1 cells appeared to be dependent on the presence of IL-12. Th2 cells, differentiated in the absence of IL-12, failed to maintain L-selectin expression. Coculture with IL-12, IL-18, IL-4, TNF-alpha, or IFN-alpha, -beta, or -gamma demonstrated a dependence on IL-12 alone for L-selectin expression. In addition, the inclusion of heat-killed Listeria monocytogenes in the cultures also maintained L-selectin expression on the Th1 cells. In all cultures, the maintenance of L-selectin on the T cell surface could be blocked by the inclusion of anti-IL-12 Abs. Analysis of the mRNA levels for L-selectin in T cells, differentiated in the presence or absence of IL-12, showed that the cytokine appears to exert its effect on L-selectin at the transcriptional level. Given the key role played by IL-12 in the differentiation of naïve T cells into the Th1 subset, the observation that IL-12 can also regulate L-selectin expression has implications for the migration of Th1 effector cells both through the lymphatic system and to sites of inflammation.

Adjuvants, Immunologic↗
PubMed2005

A crucial role for T-bet in selectin ligand expression in T helper 1 (Th1) cells.

Proinflammatory T helper 1 (Th1) cells express high levels of carbohydrate ligands for the endothelial selectins, but the molecular basis for this phenotype is incompletely understood. We document here a significant role in selectin ligand formation for the recently described Th1 transcription factor T-bet. Th1 cells generated from T-bet-/- mice showed significantly lower levels of ligands for both E-selectin and P-selectin, compared with wild-type (WT) Th1 cells. Enforced expression of T-bet in WT Th0 cells only modestly up-regulated P-selectin ligands and had no effect on E-selectin ligands. To define a mechanism for the defects observed in T-bet-/- mice, we examined expression of glycosyltransferases involved in selectin ligand biosynthesis. T-bet-/- Th1 cells expressed significantly lower levels of core 2 beta1,6 N-acetylglucosaminyltransferase I (C2GlcNAcT-I), but no differences in levels of alpha 2,3-sialyltransferase IV (ST3Gal-IV). Further, we show that T-bet is responsible for the signal transducer and activator of transcription 4 (Stat4)-independent increase in Th1 cells of fucosyltransferase VII (FucT-VII). We also identify ST3Gal-VI, which is thought to play an important role in E- and P-selectin ligand formation, as an interleukin 12 (IL-12)-regulated, T-bet-dependent gene. These data show that T-bet controls selectin ligand formation in Th1 cells via control of expression of multiple key enzymes in response to IL-12 signaling and establishes an independent transcriptional pathway for control of Th1 cell traffic.

Animals↗
PubMed1993

Th1 cell anergy and blockade in G1a phase of the cell cycle.

Human gamma-globulin (HGG)-specific Th1 cells exposed to HGG presented by chemically fixed spleen cells are blocked in G1a phase when challenged subsequently with HGG. The present study made use of the G1a blocker n-butyrate to further examine the relationship between tolerance induction and cell cycle progression. Th1 cells from primary cultures containing n-butyrate together with HGG and immunogenic, nonfixed APC lost their ability to proliferate or secrete IL-2 in HGG-stimulated secondary cultures. In contrast to their lack of responsiveness to secondary Ag challenge, Th1 cells exposed to n-butyrate and HGG proliferated normally in secondary cultures stimulated with IL-2. The suppressive effects of n-butyrate appear to require TCR occupation; Th1 cells exposed to n-butyrate in the absence of HGG did not lose their ability to proliferate in Ag-stimulated secondary cultures. In addition, although both HGG-presenting APC and IL-2 stimulate Th1 cell cycle progression into G1a, only HGG-presenting APC induced Th1 cell anergy in conjunction with n-butyrate. Unlike n-butyrate, drugs that blocked Th1 cell cycle progression in G0, G1b, or S/G2 phases did not inhibit subsequent Ag-specific proliferation by Th1 cells. Thus it appears that n-butyrate-induced G1a sequestration, in association with TCR occupancy, induces Th1 cell anergy.

Animals↗
PubMed1997

Murine CD4 T-cell response to Helicobacter infection: TH1 cells enhance gastritis and TH2 cells reduce bacterial load.

BACKGROUND & AIMS: Previous findings suggest that TH1 cellular immune responses contribute to Helicobacter-associated gastritis. To further investigate this issue, interleukin 4 gene targeted mice were infected with Helicobacter felis, and a series of adoptive transfer experiments was performed to evaluate the role of both TH1 and TH2 cells. METHODS: Antigen-specific spleen cells from immunized/challenged or nonimmunized/infected mice or CD4+ T-cell lines were transferred adoptively into naive recipients before live bacterial challenge. RESULTS: Transfer of cells from both groups of donors as well as TH1 or TH2 cell lines exacerbated gastric inflammation in the recipients. No effect on bacterial load was observed in recipients of bulk spleen cells from infected mice or recipients of TH1 cell lines. In contrast, when either a TH2 cell line or bulk cells from immunized challenged mice were transferred adoptively, recipients showed a dramatic reduction in bacterial load. Increased numbers of bacteria were also noted in interleukin 4-deficient mice. CONCLUSIONS: These data suggest a differential contribution of TH1 and TH2 cell-mediated immune responses in Helicobacter infection: one associated with the pathogenesis of disease (TH1 phenotype) and the other associated with protection from or control of infection (TH2 phenotype).

Adoptive Transfer↗
PubMed1997

Transcription mediated by NFAT is highly inducible in effector CD4+ T helper 2 (Th2) cells but not in Th1 cells.

Transcriptional factors of the NFAT family play an important role in regulating the expression of several cytokine genes during the immune response, such as the genes for interleukin 2 (IL-2) and IL-4, among others. Upon antigen stimulation, precursor CD4+ T helper (pTh) cells proliferate and differentiate into two populations of effector cells (eTh1 and eTh2), each one expressing a specific pattern of cytokines that distinguishes them from their precursors. eTh2 cells are the major source of IL-4, while gamma interferon is produced by eTh1 cells. Here we have used reporter transgenic mice to show that DNA binding and transcriptional activities of NFAT are transiently induced during the differentiation of pTh cells into either eTh1 or eTh2 cells to mediate the expression of IL-2 as a common growth factor in both pathways. However, although NFAT DNA binding is similarly induced in both eTh1 and eTh2 cells upon antigen stimulation, only the NFAT complexes present in eTh2 cells are able to mediate high-level transcription, and relatively little NFAT transcriptional activity was induced in eTh1 cells. In contrast to activated pTh cells, neither eTh1 nor eTh2 cells produced significant IL-2 upon stimulation, but the high levels of NFAT transcriptional activities directly correlate with the IL-4 production induced in response to antigen stimulation in eTh2 cells. These data suggest that activated NFAT is involved in the effector function of eTh2 cells and that the failure of eTh1 cells to produce IL-4 in response to an antigen is due, at least partially, to a failure to induce high-level transcription of the IL-4 gene by NFAT. Regulation of NFAT could be therefore a critical element in the polarization to eTh1 or eTh2.

Animals↗
PubMed2003

Lactobacilli and streptococci induce inflammatory chemokine production in human macrophages that stimulates Th1 cell chemotaxis.

Macrophages have a central role in innate-immune responses to bacteria. In the present work, we show that infection of human macrophages with Gram-positive pathogenic Streptococcus pyogenes or nonpathogenic Lactobacillus rhamnosus GG enhances mRNA expression of inflammatory chemokine ligands CCL2/monocyte chemoattractant protein-1 (MCP-1), CCL3/macrophage-inflammatory protein-1alpha (MIP-1alpha), CCL5/regulated on activation, normal T expressed and secreted, CCL7/MCP-3, CCL19/MIP-3beta, and CCL20/MIP-3alpha and CXC chemokine ligands CXCL8/interleukin (IL)-8, CXCL9/monokine induced by interferon-gamma (IFN-gamma), and CXCL10/IFN-inducible protein 10. Bacteria-induced CCL2, CCL7, CXCL9, and CXCL10 mRNA expression was partially dependent on ongoing protein synthesis. The expression of these chemokines and of CCL19 was dependent on bacteria-induced IFN-alpha/beta production. CCL19 and CCL20 mRNA expression was up-regulated by IL-1beta or tumor necrosis factor alpha (TNF-alpha), and in addition, IFN-alpha together with TNF-alpha further enhanced CCL19 gene expression. Synergy between IFN-alpha and TNF-alpha was also seen for CXCL9 and CXCL10 mRNA expression. Bacteria-stimulated macrophage supernatants induced the migration of T helper cell type 1 (Th1) cells, suggesting that in human macrophages, these bacteria can stimulate efficient inflammatory chemokine gene expression including those that recruit Th1 cells to the site of inflammation. Furthermore, L. rhamnosus-induced Th1 chemokine production could in part explain the proposed antiallergenic properties of this bacterium.

Cell Movement↗
PubMed1996

A common structural motif in immunopotentiating peptides with sequences present in human autoantigens. Elicitation of a response mediated by monocytes and Th1 cells.

We have found a common structural motif in human autoantigens, heat shock proteins and viral proteins. Peptides modelled after sequences present in those molecules were synthesized and immunomodulating properties tested. They share a core of 15 amino acid residues and a common pattern ('2-6-11' motif) characterized by requirements at fixed positions with respect to a Pro (position 6); an apolar residue or a Lys at position 2; and a Glu, Asp or Lys at position 11. Any of these peptides, when added to cultures of lymphomononuclear cells, caused the activation of monocytes manifested by a release of IL-1 alpha, IL-1 beta and TNF alpha. A release of INF gamma and IL-2 took also place; this release was abolished by anti-DR antibodies. Neither IL-4 nor IL-5 could be detected. This suggests a presentation by APCs and the appearance of cells with a Th1 phenotype. Monocytes and Th1 cells freshly obtained from 12 patients of Graves' disease, 8 of Hashimoto's disease and 8 of primary biliary cirrhosis exhibited activation features similar to those found in cells from healthy subjects incubated in the presence of peptides with a "2-6-11' motif and representing fragments of autoantigens. Their immunopotentiating properties suggest their involvement in the initiation or progression of the autoimmune response mediated by activated monocytes and Th1 cells.

Amino Acid Sequence↗
PubMed2005

Stat5a inhibits IL-12-induced Th1 cell differentiation through the induction of suppressor of cytokine signaling 3 expression.

In previous studies, we have shown that Th2 cell differentiation is diminished but Th1 cell differentiation is increased in Stat5a-deficient (Stat5a(-/-)) CD4(+) T cells. In the present study, we clarified the molecular mechanisms of Stat5a-mediated Th cell differentiation. We found that enhanced Th1 cell differentiation and the resultant IFN-gamma production played a dominant inhibitory role in the down-regulation of IL-4-induced Th2 cell differentiation of Stat5a(-/-) CD4(+) T cells. We also found that IL-12-induced Stat4 phosphorylation and Th1 cell differentiation were augmented in Stat5a(-/-) CD4(+) T cells. Importantly, the expression of suppressor of cytokine signaling (SOCS)3, a potent inhibitor of IL-12-induced Stat4 activation, was decreased in Stat5a(-/-) CD4(+) T cells. Moreover, a reporter assay showed that a constitutively active form of Stat5a but not Stat6 activated the SOCS3 promoter. Furthermore, chromatin immunoprecipitation assays revealed that Stat5a binds to the SOCS3 promoter in CD4(+) T cells. Finally, the retrovirus-mediated expression of SOCS3 restored the impaired Th cell differentiation of Stat5a(-/-) CD4(+) T cells. These results suggest that Stat5a forces the Th1/Th2 balance toward a Th2-type by preventing IL-12-induced Th1 cell differentiation through the induction of SOCS3.

Animals↗
PubMed2001

Induction of anergy in Th1 cells associated with increased levels of cyclin-dependent kinase inhibitors p21Cip1 and p27Kip1.

Th1 cells exposed to Ag and the G(1) blocker n-butyrate in primary cultures lose their ability to proliferate in Ag-stimulated secondary cultures. The ability of n-butyrate to induce anergy in Ag-stimulated, but not resting, Th1 cells was shown here to be blocked by cycloheximide. Subsequent experiments to delineate the nature of the protein apparently required for n-butyrate-induced Th1 cell anergy focused on the role of cyclin-dependent kinase (cdk) inhibitors p21(Cip1) and p27(Kip1). Normally, entry into S phase by Th1 cells occurs around 24 h after Ag stimulation and corresponds with relatively low levels of both p21(Cip1) and p27(Kip1). However, unlike control Th1 cells, anergic Th1 cells contained high levels of both p21(Cip1) and p27(Kip1) when examined 24 h after Ag stimulation. The increase in p21(Cip1) observed in Ag-stimulated anergic Th1 cells appeared to be initiated in primary cultures. In contrast, the increase in p27(Kip1) observed in these anergic Th1 cells appears to represent a re-expression of the protein much earlier than control cells following Ag stimulation in secondary cultures. The anergic Th1 cells contained functionally active cdk inhibitors capable of inhibiting the activity of both endogenous and exogenous cdks. Consequently, it appears that n-butyrate-induced anergy in Th1 cells correlated with the up-regulation of p21(Cip1) and perhaps the downstream failure to maintain low levels of p27(Kip1). Increased levels of both p21(Cip1) and p27(Kip1) at the end of G(1) could prevent cdk-mediated entry into S phase, and thus help maintain the proliferative unresponsiveness found in the anergic Th1 cells.

Animals↗