Th1 T-cell Research Articles

CXCR4/CD184 Immunoreactivity in T-Cell Non-Hodgkin Lymphomas With an Overall Th1- Th2+ Immunophenotype

We performed an immunohistochemical analysis of CXCR4/CD184 expression in frozen and paraffin-embedded sections of human peripheral T-cell lymphomas that exhibit a composite Th1 T-cell–like or Th2 T-cell–like immunophenotype, based on expression of Th1-associated markers (CXCR3, CD134/OX40, and CD69) and Th2-associated markers (CD30 and CCR4). In 66 cases examined, CXCR4/CD184 expression correlated significantly with immunoreactivity for other markers of Th2 differentiation (P < .0001). Anaplastic large cell lymphoma, which typically expresses markers of Th2 differentiation, was immunoreactive for CXCR4/CD184 in 22 (88%) of 25 cases. Tumors previously identified as exhibiting a composite Th1-like immunophenotype, which include angioimmunoblastic lymphoma, lymphoepithelioid lymphoma, and other peripheral T-cell lymphomas now termed unspecified, were positive for CXCR4/CD184 in 7 (17%) of 41 cases. These results are consistent with previous findings that a subset of peripheral T-cell lymphomas can be divided into Th1-like and Th2-like categories based on immunoreactivity with a limited set of markers. Our findings also suggest that CXCR4/CD184, which is expressed by a number of malignant neoplasms and may have a role in tumor metastasis, may have a similar function in CXCR4+ T-cell non-Hodgkin lymphomas.

Intracellular cytokine profiles by peripheral blood CD3+ T-cells in patients with classical Hodgkin lymphoma.

The intracellular profiles of T helper type 1 (Th1) and T helper type 2 (Th2) T-cell cytokines by peripheral blood (PB) CD3+ T-cells in patients with classical Hodgkin lymphoma (HL) has not been investigated before. The present study examines the cytoplasmic production of interleukin (IL) 2, 4, 10, tumour necrosis factor alpha (TNFalpha), and interferon gamma (IFNgamma) by activated PB CD3+ T-cells and compares them with the profiles observed with normal individuals. We report a significantly lower mean level of intracellular IL2, TNFalpha and IFNgamma at any time post-cell activation in cells isolated from patients with HL compared with the normal control group. In contrast, the mean level of cytoplasmic IL4 was significantly higher in the HL compared with the control group. No significant difference between the two groups was observed with IL10. In the HL patient group, there was a significantly higher percentage of CD3+CD8+ T-cells that synthesised IL4 compared with the CD3+CD4+ subpopulation, no such difference was observed in normal controls. The intensity of IL4 (expressed as relative median fluorescence) was significantly higher in the CD3+CD8+ cells of the patients with HL compared with the CD3+CD4+ sub-population, or with normal CD3+CD8+ cells. In conclusion, there is reduced intracellular IL2, TNFalpha and IFNgamma and increased cytoplasmic IL4 production by activated PB T-cells in patients with HL. The CD3+CD8+ sub-population is responsible for the increased levels of IL4.

HLA-DP-unrestricted TNF-alpha release in beryllium-stimulated peripheral blood mononuclear cells.

Berylliosis is a granulomatous disorder of the lung caused by inhalation of beryllium (Be) and dominated by the accumulation of CD4+ T-helper (Th)1 memory T-cells proliferating in response to Be in the lower respiratory tract. Two gene markers have been associated with susceptibility to berylliosis: 1) the human leucocyte antigen (HLA)-DP gene whose allelic variants, carrying glutamate in position 69 of the beta-chain (HLA-DPGlu69), can bind Be directly and present it to interferon (IFN)-gamma releasing Th1 T-cell clones from patients with berylliosis; and 2) the cytokine gene tumour necrosis factor (TNF)-alpha which has been shown to increase berylliosis risk independent of HLA-DPGlu69. In order to determine whether TNF-alpha release was triggered by Th1 T-cell activation by Be stimulation in the context of HLA-DPGlu69 molecules, the proliferation of BeSO4-stimulated blood mononuclear cells and the release of IFN-gamma, TNF-alpha, RANTES (regulated on activation normal T-cell expressed and secreted), granulocyte-macrophage colony-stimulating factor, interleukin (IL)-4, IL-6, IL-8, IL-10 and IL-12 by BeSO4-stimulated blood mononuclear cells was quantified in 11 individuals with berylliosis using an anti-HLA-DP antibody as a probe for HLA-DP restricted T-cell activation. While proliferation and IFN-gamma release were completely abrogated by HLA-DP inhibition (inhibition with anti-HLA-DP monoclonal antibody (mAb): 88+/-16 and 77+/-16%, respectively; anti-HLA-DR: 29+/-38 and 14+/-10%, respectively), the release of TNF-alpha was not (inhibition with anti-HLA-DP mAb: 8.9+/-7.8%). No other cytokine was detected at significant levels. Moreover, Be was able to induce TNF-alpha production in healthy control subjects not exposed to Be in the absence of T-cell proliferation and IFN-gamma production. In conclusion, these data suggest that the tumour necrosis factor-alpha response of mononuclear cells is independent of the activation of beryllium-specific human leucocyte anitgen-DP restricted T-cells, which is consistent with the finding that the tumour necrosis factorA2 and the human leucocyte anitgen-DPGlu69 genetic markers are independently interacting in increasing berylliosis risk.

Effect of antioxidants on the immune response of Helicobacter pylori

Antioxidants are substances capable of inhibiting oxidation. In chronic diseases, inflammatory response cells produce oxygen free radicals. Oxygen free radicals cause DNA damage, and this may lead to gene modifications that might be carcinogenic. Chronic Helicobacter pylori infection causes the production of DNA-damaging free radicals. In recent years, various groups have studied the effects of antioxidants, especially on H. pylori-associated gastric cancer. In most of the studies, it has been shown that H. pylori infection does affect the level of antioxidants measured in the gastric juice, but there are also controversial results. Recent experimental studies, both in vivo and in vitro, have shown that vitamin C and astaxanthin, a carotenoid, are not only free radical scavengers but also show antimicrobial activity against H. pylori. It has been shown that astaxanthin changes the immune response to H. pylori by shifting the Th1 response towards a Th2 T-cell response. Very few experimental studies support the epidemiologic studies, and further studies are needed to describe the effect and the mechanism of antioxidants in the H. pylori immune response.

The immunology of alopecia areata and potential application to novel therapies

There is strong evidence indicating alopecia areata (AA) is a tissue-specific, autoimmune disease. Hair loss is associated with a perifollicular lymphocytic infiltrate made up primarily of CD4+ cells, associated with a CD8+ intrafollicular infiltrate. Evidence of immune activation includes expression of human leukocyte antigen (HLA)-DR, HLA-A,B,C, and intercellular adhesion molecule (ICAM)-1 on the follicular epithelium. It is likely that the follicular expression of HLA-DR and ICAM-1 is induced by interferon (IFN)-γ produced by T cells. Antibodies to follicular epithelium are often present, but their significance is not known. Lesional scalp from AA patients grafted onto nude mice regrows hair coincident with a loss of infiltrating lymphocytes from the graft. It is possible to transfer hair loss to human scalp explants on severe combined immunodeficiency (SCID) mice by injection of lesional T cells. Neuropeptides produced by cutaneous nerves may modify immune reactivity and influence disease. In particular, low levels of the calcitonin gene-related peptide (CGRP) may have a role in initiation of the condition by inducing immune hyperresponsiveness and vasoconstriction. Best evidence is that AA is a mediated by a TH1 T-lymphocyte response. Translation of these data into potential new therapies is discussed.

Hydrolysis of interleukin-12 by Porphyromonas gingivalis major cysteine proteinases may affect local gamma interferon accumulation and the Th1 or Th2 T-cell phenotype in periodontitis.

Porphyromonas gingivalis cysteine proteinases (gingipains) have been associated with virulence in destructive periodontitis, a disease process variously considered to represent an unregulated stimulation of either T helper type 1 (Th1)- or Th2-type cells. Critical in maintaining Th1 activity is the response of T lymphocytes to environmental interleukin 12 (IL-12) in the form of up-regulation of gamma interferon (IFN-gamma) production. Here we demonstrate that in the presence or absence of serum, gingipains were able to hydrolyze IL-12 and reduce the IL-12-induced IFN-gamma production from CD4+ T cells. However, the induction of IL-12 receptors on T cells by gingipains did not correlate with the enhancement of IFN-gamma production. The gingipains cleaved IL-12 within the COOH-terminal region of the p40 and p35 subunit chains, which leads to IL-12 inactivity, whereas IL-2 in these assays was not affected. Inactivation of IL-12 by the gingipains could disrupt the cytokine balance or favor Th2 activities in the progression of periodontitis.

Suppression of immune surveillance in melanoma

Numerous reports of IL-10 cytokine secretion by tumor infiltrating cells indicate there is suppression of immune surveillance within the milieu of many melanomas. In this paper we have outlined the suppressor system that best fits the published data. The regulatory system is composed of CD4+ T-lymphocytes which have been activated and programmed to secrete Th2 cytokines. Initially these cells do not secrete cytokines, but subsequently they enter an IL-10 secretory phase as a result of T-T cell interaction. After activation, Th1 programmed T-cells express MHC class II molecules and B7 second signals. When these Th1 T-cells express MHC II molecules containing ‘self’ polypeptides coupled with faulty B7-H1 second signals they are subject to inactivation by Th2 T-cells. If this system can be inactivated, immunotherapy of melanoma will be more successful. If an antigen can be discovered that stimulates sensitized Th2 T-cells without stimulating Th1 T-cells, this antigen, followed with cyclophosphamide, can be used to destroy the Th2 T-cells in the course of both active and passive immunotherapy. Solubilized MHC II molecules with appropriate ‘self’ polypeptides should qualify as such an antigen. We postulate such an antigen can be prepared using poliovirus 1 (Sabin) to lyse melanoma tissue cultures.

T-cell Tolerance and Autoimmune Diabetes

Herein we describe the major signaling events that occur in T-cells upon T-cell receptor (TCR) engagement, and the mechanisms responsible for the induction of T-cell anergy that may ultimately lead to the development of immunospecific therapies in T-cell mediated autoimmune diseases. A new type of antigen presenting molecule (dimeric MHC class-II/peptide, DEF) endowed with antigen-specific immunomodulatory effects such as induction of Th2 polarization and T-cell anergy is also described as a potential antidiabetogenic agent. According to our preliminary results, the MHC II/peptide-based approach may provide rational grounds for further development of antigen-specific immunotherapeutic agents such as human-like MHC II/peptide chimeras endowed with efficient down-regulatory effects in CD4 T-cell-mediated autoimmune diseases such as Type 1 diabetes, multiple sclerosis, primary biliary cirrhosis, and rheumatoid arthritis.

Regulation of experimental mucosal inflammation

Studies conducted over the past 10 years have provided ample evidence that many types of inflammations arising from basic abnormalities of immune regulation are ultimately ‘funneled’ through a Th1 or Th2 T cell-mediated immune reaction. Thus, by understanding these types of reactions and, in particular, by identifying their natural checkpoints, one can control the inflammation regardless of its more basic causes. A case in point is the inflammatory disease of the intestine known as Crohn disease, a disease now thought to be due to one or more abnormalities leading to an excessive immune response to elements of the bacterial microflora of the gut. Both in murine models and by study of Crohn disease itself, we have shown that Crohn inflammation is due to a Th1 T-cell abnormality involving overproduction of interleukin (IL)-12, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α. In addition, we and others have shown that treatment of mice with anti-IL-12 or other agents that downregulate the level of IL-12 secretion can have a dramatic effect on the inflammation. This is because anti-IL-12 administration leads to apoptosis of activated Th1 T cells. A second checkpoint of Th1 T-cell-mediated inflammation involves its downregulation by the suppressor cytokine, transforming growth factor (TGF)-β. We have been delivering TGF-β to mice with experimental intestinal inflammation, using several novel approaches. In particular, we have successfully treated such mice with intranasally administered DNA encoding active TGF-β. Another approach currently under investigation is delivery of TGF-β by gene therapy. These and other developments in the understanding of inflammation paint a bright future for cytokine-based therapeutic agents. It is now apparent that these therapies are not only effective and safe but also potentially longlasting.

Th1 T-CELL AND MONOCYTE DEFECTS

Mutations predisposing to infections with intracellular pathogens and affecting Th1 T-cells and monocytes have been identified in the past few years. In this article, the authors review the interaction of T cells and monocytes in the context of host defense against intracellular pathogens. Known genetic defects in these pathways are summarized.

Lupus nephritis and the anti-phospholipid antibody syndrome in pregnancy

Lupus nephritis and the anti-phospholipid antibody syndrome in pregnancy

Cord blood dendritic cells predominantly display a PRECURSOR-DC2-like phenotype but induce TH1 t-cell responses

T cells are effector cells in Graft-versus-Host Disease (GvHD) and the pivotal role of dendritic cells (DC) in T cell activation is established. Nevertheless, little is known about the involvement of graft DC in the initiation of GvHD. Following allogeneic cord blood (CB) transplantation, the incidence and severity of acute GvHD is low. To determine whether this is associated with differences in the DC compartment, cord blood dendritic cells were studied. CBDC were enriched by depletion of lineage marker positive cells. They showed potent T cell stimulatory activity and induced IL-2 and IFN-gamma but no IL-4 in allogeneic CB T cells, thus a TH1-type of response. Phenotypic analysis revealed two CBDC subpopulations. The main population, accounting for 84.5±14.2% (n=47) of CBDC in lin− enriched preparations was lin−, HLA-DR+, CD4+, CD11c−, CD33−, CD45RA+, CD54+, CD58−/dim, CD86−, and CD123bright. The minor subpopulation showed in lindim, HLA-DRbright, CD4−/low, CD11c+, CD33+, CD45RAlow, CD54−/dim, CD58dim, CD86dim, and CD123+ phenotype. Both CBDC subpopulations expressed CD11a, CD50, CD116 and low levels of CD102, but lacked expression of CD40, CD45R0, CD80 and CD83. The presence of the minor, CD11c+ subpopulation varied widely, ranging from 0 to 58% of CBDC. Its frequency was inversely correlated with the gestational age. Thus, CBDC predominantly resemble precursor-DC2 in phenotype, but stimulate a THl-type of T cell response.

LFA-3 Plasmid DNA Enhances Ag-Specific Humoral- and Cellular-Mediated Protective Immunity against Herpes Simplex Virus-2 in Vivo: Involvement of CD4+ T Cells in Protection

Adhesion molecules are important for cell trafficking and delivery of secondary signals for stimulation of T cells and antigen-presenting cells (APCs) in a variety of immune and inflammatory responses. Adhesion molecules lymphocyte function-associated antigen (LFA)-1 and CD2 on T cells recognize intercellular adhesion molecule (ICAM)-1 and LFA-3 on APCs, respectively. Recent studies have suggested that these molecules might play a regulatory role in antigen-specific immune responses. To investigate specific roles of adhesion molecules in immune induction we coimmunized LFA-3 and ICAM-1 cDNAs with a gD plasmid vaccine and then analyzed immune modulatory effects and protection against lethal herpes simplex virus (HSV)-2 challenge. We observed that gD-specific IgG production was enhanced by LFA-3 coinjection. However, little change in IgG production was observed by ICAM-1 coinjection. Furthermore, both Th1 and Th2 IgG isotype production was driven by LFA-3. LFA-3 also enhanced Th cell proliferative responses and production of interleukin (IL)-2, interferon-γ, IL-4, and IL-10 from splenocytes. In contrast, ICAM-1 showed slightly increasing effects on T-cell proliferation responses and cytokine production. β-Chemokine production (RANTES, MIP-1α, and MCP-1) was also influenced by LFA-3 or ICAM-1. When animals were challenged with a lethal dose of HSV-2, LFA-3-coimmunized animals exhibited an enhanced survival rate, as compared to animals given ICAM-1 or gD DNA vaccine alone. This enhanced protection appears to be mediated by CD4+ T cells, as determined by in vitro and in vivo T-cell subset deletion. These studies demonstrate that adhesion molecule LFA-3 can play an important role in generating protective antigen-specific immunity in the HSV model system through increased induction of CD4+ Th1 T-cell subset.

Molecular aspects of T-cell differentiation.

Differentiated T helper 1 (Th1) and T helper 2 (Th2) T-cells show striking differences in their patterns of cytokine expression. This process is initiated by stimulation with antigen and the cytokines IL-12 and IL-4, respectively, and requires antigen-induced transcription factors such as NFAT and cytokine-induced transcription factors such as STAT4, induced by IL-12, and STAT6, induced by IL-4. This results in induction and maintained expression of subset-specific transcription factors including T-bet in Th1 cells and GATA3 in Th2 cells, which are involved in ensuring the commitment of T-cells to Th1 or Th2 lineages. Here we review the signalling pathways and transcription factors that mediate T-cell differentiation, and describe the epigenetic changes in chromatin structure, locus accessibility and DNA methylation that are known to accompany this process.

The CC-chemokine receptor 5 (CCR5) is a marker of, but not essential for the development of human Th1 cells.

The CC-chemokine receptor 5 (CCR5) has recently been described as a surface marker of human T cells producing type 1 (Th1) cytokines. Here we confirm that CCR5 is expressed on human Th1 but not on Th2 T-cell clones. Using intracellular cytokine staining, we show that alloantigen specific CD4+ T-cell lines derived from a CCR5-deficient individual (delta32 allele homozygote) contain high numbers of both interferon gamma (IFN-gamma) and interleukin (IL)-2 producing cells, low numbers of IL-10 producing cells and no IL4 or IL-5 producing cells when stimulated with phorbol ester and ionomycin in vitro. These results were similar to those obtained from alloantigen specific CD4+ T-cell lines derived from CCR5 expressing individuals. An enzyme-linked immunoabsorbent assay (ELISA) confirmed that the Th1 cytokine-positive cells from the CCR5-deficient individual were able to produce equal amounts of cytokines when compared to T-cell lines from CCR5-expressing individuals, These results demonstrate that CCR5-negative T cells display the same capacity of Th1 T-cell differentiation as T cells derived from CCR5-expressing individuals. Thus, CCR5 expression is not essential for differentiation of human Th1 T cells.

Dendritic cells in allergy.

Dendritic cells in allergy.

Modulation of Airway Inflammation by CpG Oligodeoxynucleotides ina Murine Model of Asthma

1. Kline JN, 2. Waldschmidt TJ, 3. Businga TR, 4. et al. (1998) J Immunol. 160:2555–2559. [OpenUrl][1][Abstract/FREE Full Text][2] #### Background Asthmatics and allergic patients have a surplus of Th-2 T-cells, which are responsible for the production of cytokines that drive the allergic and asthmatic states. Nonallergic, nonasthmatics do not routinely demonstrate a Th-2 profile. Because all children with normal immunity produce Th-1 T-cells, necessary for immune responsiveness to bacterial and viral antigens, it has been speculated that allergic children may somehow be more geared to … [1]: {openurl}?query=rft.jtitle%253DThe%2BJournal%2Bof%2BImmunology%26rft.stitle%253DJ.%2BImmunol.%26rft.issn%253D0022-1767%26rft.aulast%253DKline%26rft.auinit1%253DJ.%2BN.%26rft.volume%253D160%26rft.issue%253D6%26rft.spage%253D2555%26rft.epage%253D2559%26rft.atitle%253DCutting%2BEdge%253A%2BModulation%2Bof%2BAirway%2BInflammation%2Bby%2BCpG%2BOligodeoxynucleotides%2Bin%2Ba%2BMurine%2BModel%2Bof%2BAsthma%26rft_id%253Dinfo%253Apmid%252F9510150%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [2]: /lookup/ijlink?linkType=ABST&journalCode=jimmunol&resid=160/6/2555&atom=%2Fpediatrics%2F104%2FSupplement_2%2F373.2.atom

Dynamic Analysis of T-Lymphocyte Function in Relation to Hepatopathologic Changes and Effect of Interleukin-12 Treatment in Mice Infected with Schistosoma japonicum

We analyzed the dynamics of splenic T-lymphocyte function in relation to hepatopathologic changes in C3H/Hc mice, experimentally infected with Schistosoma japonicum. Vigorous granuloma formation was observed at 7 wk postinfection. At 10 wk postinfection, granuloma formation entered into the down-modulation stage, as represented by the diminished granuloma size. The Th2 response was activated when eggs appeared in the liver, whereas Th1 responses were depressed and the proliferation of T lymphocytes was decreased. The level of IgG antibodies to the worm and egg antigens rose continually after infection. Interleukin-12 treatment of infected mice inhibited Th2 responses and T-cell proliferation, decreased granuloma formation and fibrosis, but had no effect on the fecundity of the worms. These data suggest that egg deposition is the major factor driving Th2 responses, depressing Th1 cytokine expression as well as T-cell proliferation in S. japonicum-infected mice.

Contribution of T cells to the development of autoimmune diabetes in the NOD mouse model.

The nonobese diabetic (NOD) mouse spontaneously develops an autoimmune diabetes that shares many immunogenetic features with human insulin-dependent diabetes mellitus (IDDM), type 1 diabetes. The mononuclear cell infiltrates in the islet, which results in the development of insulitis (a prerequisite step for the development of diabetes) are primarily composed of T cells. It is now well accepted that these T cells play important roles in initiating and propagating an autoimmune process, which in turn destroys insulin-producing islet beta cells in the pancreas. T cells are subdivided into CD4+ helper T cells and CD8+ cytotoxic T cells. CD4+ T cells are further subdivided into Th1 and Th2 cells based on profiles of cytokine production, and these two T-cell populations counterregulate each other. Because many autoimmune diseases are Th1 T-cell mediated, current studies have focused on manipulating the Th1/Th2 imbalance to suppress the autoimmune process in the NOD model. Furthermore, the incidence of disease is much higher in females than that in males, suggesting an involvement of sex-steroid hormones in the development of diabetes. Understanding insights of the mechanism of immune-mediated islet cell destruction and the interaction between the immune and the neuroendocrine system may, therefore, provide new therapeutic means of preventing this chronic debilitating disease.

The role of new asthma treatments

Inhaled corticosteroid therapy remains the basis for the treatment of chronic asthma. Recent understanding of its use includes the benefits of early introduction, and of its plateaued dose-benefit effects. Additional beneficial effects on asthma control and prevention of asthma exacerbations can be obtained by combining middle-to high-dose inhaled corticosteroid with long-acting β-agonists and slow-release theophylline. Leukotriene inhibitors, particularly leukotriene receptor antagonists, are novel treatments that may also be combined with inhaled steroid therapy. Although current asthma treatments are very effective, a subgroup of asthma patients (difficult or therapy-resistant asthma) do not respond adequately to these treatments and need maintained oral corticosteroid therapy. New asthma treatments are particularly needed for this group. New treatments for asthma include more potent topical corticosteroids which have less potential for side-effects, inhibition of eosinophil chemotaxis and activation such as anti-IL-5, anti-eotaxin, eotaxin receptor antagonist, anti-VL-A4, anti-IgE therapy, restoring Th-1/Th-2 balance either by increasing Th-1 or reducing Th-2 T-cell activity, anti-inflammatory cytokines such as IL-10, and specific inhibitors of PDE4. These treatments may be considered as either controllers, remitters (inducing remission of disease), or preventors according to their modes of action and their clinical effects. Currently, there does not appear to be any prospect of a cure for asthma.