scholarly journals Control of T helper cell differentiation through cytokine receptor inclusion in the immunological synapse

2009 ◽  
Vol 206 (4) ◽  
pp. 877-892 ◽  
Author(s):  
Roberto A. Maldonado ◽  
Michelle A. Soriano ◽  
L. Carolina Perdomo ◽  
Kirsten Sigrist ◽  
Darrell J. Irvine ◽  
...  
Keyword(s):  
Immunological Synapse ◽  
Nuclear Translocation ◽  
Interferon Γ ◽  
Membrane Receptors ◽  
Interleukin 4 ◽  
T Helper ◽  
Tcr Signaling ◽  
Effector Cells ◽  
Antigen Presenting ◽  
Th2 Differentiation

The antigen recognition interface formed by T helper precursors (Thps) and antigen-presenting cells (APCs), called the immunological synapse (IS), includes receptors and signaling molecules necessary for Thp activation and differentiation. We have recently shown that recruitment of the interferon-γ receptor (IFNGR) into the IS correlates with the capacity of Thps to differentiate into Th1 effector cells, an event regulated by signaling through the functionally opposing receptor to interleukin-4 (IL4R). Here, we show that, similar to IFN-γ ligation, TCR stimuli induce the translocation of signal transducer and activator of transcription 1 (STAT1) to IFNGR1-rich regions of the membrane. Unexpectedly, STAT1 is preferentially expressed, is constitutively serine (727) phosphorylated in Thp, and is recruited to the IS and the nucleus upon TCR signaling. IL4R engagement controls this process by interfering with both STAT1 recruitment and nuclear translocation. We also show that in cells with deficient Th1 or constitutive Th2 differentiation, the IL4R is recruited to the IS. This observation suggest that the IL4R is retained outside the IS, similar to the exclusion of IFNGR from the IS during IL4R signaling. This study provides new mechanistic cues for the regulation of lineage commitment by mutual immobilization of functionally antagonistic membrane receptors.

scholarly journals Interleukin (IL)-6 Directs the Differentiation of IL-4–producing CD4+ T Cells

1997 ◽  
Vol 185 (3) ◽  
pp. 461-470 ◽  
Author(s):  
Mercedes Rincón ◽  
Juan Anguita ◽  
Tetsuo Nakamura ◽  
Erol Fikrig ◽  
Richard A. Flavell
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Antigen Presenting Cells ◽  
Interferon Γ ◽  
T Helper Cell ◽  
Th2 Cells ◽  
T Helper ◽  
Key Factor ◽  
Antigen Presenting ◽  
Potent Factor

Interleukin (IL)-4 is the most potent factor that causes naive CD4+ T cells to differentiate to the T helper cell (Th) 2 phenotype, while IL-12 and interferon γ trigger the differentiation of Th1 cells. However, the source of the initial polarizing IL-4 remains unclear. Here, we show that IL-6, probably secreted by antigen-presenting cells, is able to polarize naive CD4+ T cells to effector Th2 cells by inducing the initial production of IL-4 in CD4+ T cells. These results show that the nature of the cytokine (IL-12 or IL-6), which is produced by antigen-presenting cells in response to a particular pathogen, is a key factor in determining the nature of the immune response.

scholarly journals T helper type 1–specific Brg1 recruitment and remodeling of nucleosomes positioned at the IFN-γ promoter are Stat4 dependent

2006 ◽  
Vol 203 (6) ◽  
pp. 1493-1505 ◽  
Author(s):  
Fuping Zhang ◽  
Mark Boothby
Keyword(s):  
Interferon Γ ◽  
T Cell Differentiation ◽  
T Helper ◽  
Nucleosome Remodeling ◽  
Specific Manner ◽  
Ifn Γ ◽  
Calcineurin Phosphatase ◽  
Th2 Differentiation ◽  
Early Recruitment

Transcriptional competence of the interferon-γ (IFN-γ) locus is enhanced as Th1 effectors develop from naive CD4 T lymphocytes; conversely, this gene is repressed during Th2 differentiation. We now show that the Switch (Swi)–sucrose nonfermenter (SNF) component Brahma-related gene 1 (Brg1) is recruited, and positioned nucleosomes are remodeled, in a Th1-specific manner that is dependent on the transcription factor Stat4 and calcineurin phosphatase activity. Interference with specific components of mammalian Swi–SNF complexes decreased CD4 T cell differentiation into IFN-γ–positive Th1 cells. These findings reveal a collaborative mechanism of IFN-γ gene regulation during Th1 differentiation and suggest that a Th1-specific chromatin structure is created by early recruitment of Swi–SNF complexes and nucleosome remodeling dependent on Stat4 and calcineurin activation.

In vitro growth inhibition of a broad spectrum of tumor cell lines by activated human dendritic cells

Blood ◽  
2000 ◽  
Vol 95 (7) ◽  
pp. 2346-2351 ◽  
Author(s):  
Andrei I. Chapoval ◽  
Koji Tamada ◽  
Lieping Chen
Keyword(s):  
Dendritic Cells ◽  
Growth Inhibition ◽  
Wide Spectrum ◽  
Human Tumor ◽  
Interferon Γ ◽  
Interleukin 4 ◽  
Tumor Resistance ◽  
Blood Monocytes ◽  
Effector Cells

Dendritic cells (DCs) are critical subsets of leukocytes providing antigen presentation for initiation of humoral and cellular immune responses. Their role as effector cells in tumor resistance, however, is less known. We report here that human DCs generated by culturing plastic-adherent peripheral blood monocytes in the presence of granulocyte-monocyte colony–stimulating factor (GM-CSF) and interleukin-4 have potent growth-inhibition activity in vitro on a wide spectrum of human tumor lines of different tissue origin. Proinflammatory stimuli lipopolysaccharide (LPS) and interferon-γ, but not tumor necrosis factor– and CD40 signaling, can further enhance DC-mediated inhibition of tumor growth. The growth inhibition requires contact between DCs and tumor cells while LPS treatment enhances the antitumor activity in DC culture supernatants. Our results suggest that in addition to their predominant role as regulatory cells, activated DCs are also potential effector cells in tumor immunity.

scholarly journals Interleukin-4 supports interleukin-12-induced proliferation and interferon-γ secretion in human activated lymphoblasts and T helper type 1 cells

Immunology ◽  
2006 ◽  
Vol 119 (1) ◽  
pp. 43-53 ◽  
Author(s):  
Martin A. Kriegel ◽  
Theresa Tretter ◽  
Norbert Blank ◽  
Martin Schiller ◽  
Christoph Gabler ◽  
...  
Keyword(s):  
Interferon Γ ◽  
Interleukin 4 ◽  
Interleukin 12 ◽  
T Helper ◽  
Helper Type

scholarly journals Expansion and long-range differentiation of the NKT cell lineage in mice expressing CD1d exclusively on cortical thymocytes

2005 ◽  
Vol 202 (2) ◽  
pp. 239-248 ◽  
Author(s):  
Datsen G. Wei ◽  
Hyunji Lee ◽  
Se-Ho Park ◽  
Lucie Beaudoin ◽  
Luc Teyton ◽  
...  
Keyword(s):  
Cell Lineage ◽  
Cell Types ◽  
Interferon Γ ◽  
Interleukin 4 ◽  
Thymic Epithelial Cells ◽  
Nkt Cell ◽  
Extensive Cell ◽  
Cell Type Specific ◽  
Necessary And Sufficient ◽  
Antigen Presenting

Unlike conventional major histocompatibility complex–restricted T cells, Vα14-Jα18 NKT cell lineage precursors engage in cognate interactions with CD1d-expressing bone marrow–derived cells that are both necessary and sufficient for their thymic selection and differentiation, but the nature and sequence of these interactions remain partially understood. After positive selection mediated by CD1d-expressing cortical thymocytes, the mature NKT cell lineage undergoes a series of changes suggesting antigen priming by a professional antigen-presenting cell, including extensive cell division, acquisition of a memory phenotype, the ability to produce interleukin-4 and interferon-γ, and the expression of a panoply of NK receptors. By using a combined transgenic and chimeric approach to restrict CD1d expression to cortical thymocytes and to prevent expression on other hematopoietic cell types such as dendritic cells, macrophages, or B cells, we found that, to a large extent, expansion and differentiation events could be imparted by a single-cognate interaction with CD1d-expressing cortical thymocytes. These surprising findings suggest that, unlike thymic epithelial cells, cortical thymocytes can provide unexpected, cell type–specific signals leading to lineage expansion and NKT cell differentiation.

Peripheral Blood T-Helper Cells and Eosinophil Populations in Patients with Atopic and Nonatopic Chronic Rhinosinusitis

2017 ◽  
Vol 31 (1) ◽  
pp. e8-e12 ◽  
Author(s):  
Zhenxiao Huang ◽  
Jayakar V. Nayak ◽  
Yan Sun ◽  
Qian Huang ◽  
Bing Zhou
Keyword(s):  
Chronic Rhinosinusitis ◽  
Peripheral Blood ◽  
T Helper Cells ◽  
Nasal Polyps ◽  
Interferon Γ ◽  
Interleukin 4 ◽  
Th2 Cells ◽  
T Helper ◽  
Helper Cells ◽  
Th1 And Th2

Background Analysis of recent research indicated that T-helper cells may play an important role in the pathogenesis of chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP). Objective The purpose of this study was to investigate the peripheral blood Th1 and Th2 cells and eosinophil population in patients with CRS. Methods Peripheral blood samples were obtained from nine nonatopic controls, 37 patients with CRSsNP, and 66 patients with CRSwNP. The samples were then analyzed by flow cytometry analysis (Th1 cell [CD4+, interleukin 4−, interferon γ+]; and Th2 cell [CD4+, interleukin 4+, interferon γ−]). The patients were stratified into four groups based on their allergic status by using skin-prick test results and immunoglobulin E level measurements as the following: (1) nonatopic CRSsNP, (2) nonatopic CRSwNP, (3) atopic CRSsNP, and (4) atopic CRSwNP. Eosinophil counts were also compared. The severity of nasal diseases in these patients was assessed via the Lund-Mackay score. Results No significant differences in peripheral blood Th1 and Th2 cells were found among all the atopic, nonatopic CRS groups, and the nonatopic control groups. Peripheral blood eosinophil levels in atopic CRSwNP were significantly elevated compared with the nonatopic controls (p < 0.05), but no significant difference was found among all atopic and nonatopic CRS groups. Conclusion Analysis of our data demonstrated that a proportion of systemic Th1- and Th2-skewed lymphocytes in all CRS groups were similar to that in healthy subjects, irrespective of atopic status. The patients with CRSwNP and with atopy but not the patients with CRSsNP and with atopy demonstrated systemic eosinophilic inflammation. Further studies are needed to investigate underlying pathophysiologic mechanism or endotypes.

Redirection of CMV Specific CTL towards B-CLL Via CD20 Targeted HLA/CMV Complexes.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 449-449 ◽  
Author(s):  
Rogier Mous ◽  
Philip Savage Savage ◽  
Ester BM Remmerswaal ◽  
Rene A.W. van Lier ◽  
Eric Eldering ◽  
...  
Keyword(s):  
T Cells ◽  
B Cell ◽  
Immunological Synapse ◽  
Ex Vivo ◽  
Cytotoxic T Cells ◽  
Interferon Γ ◽  
Lymphocytic Leukemia ◽  
Viral Immunity ◽  
Single Chain ◽  
Effector Cells

Abstract Because B cell chronic lymphocytic leukemia (B-CLL) can not be cured with current therapies, but in general has a slow progression and rather long median survival, it is considered an attractive candidate for active T cell mediated immunotherapy. However B-CLL cells have poor antigen presenting capacity because they express low levels of co-stimulatory molecules. Moreover, most immunotherapeutic strategies require knowledge of the eliciting tumor antigen and/or ex vivo manipulation of patient cells. To circumvent these drawbacks we aim to redirect existing viral immunity towards B-CLL. Previously, we have shown that in patients with B-CLL considerably expanded numbers of cytomegalovirus (CMV)-specific CD45RA+CD27 CD8+ cytotoxic T cells are present (W. Mackus et al. Blood2003; 102:1057). These cells are potent cytotoxic effector cells when directed against B-CLL cells loaded with CMV peptide (A.Kater et al. Br.J. Haematol.2004; 126:512). In the current study, we apply a novel bridging reagent to redirect CMV-specific CTL to specifically target B-CLL. The targeting complex is composed of a streptavidin fused anti-CD20 single chain variable fragment (scFv) in combination with biotinylated MHC class I molecules containing CMV pp65 peptide (HLA/CMV). We demonstrate that this complex is stable on the cell surface for ≥24 hours, and that B-CLL cells coated with this CD20-HLA/CMV complex can be lysed by autologous CMV-specific CD8+ CTL with similar efficiency as B-CLL cells directly loaded with CMV-peptide. Killing occurs at scFv CD20 concentrations of ≥100 ng ml−1 and HLA/CMV concentrations of ≥20 ng ml−1. Lysis of CD20-HLA/CMV complex coated CLL cells could not be blocked by anti-LFA1 antibodies, in contrast to B-CLL cells directly loaded with CMV-peptide, indicating a different immunological synapse. HLA-A2 positive B-CLL cells coated with HLA-B7 /CMV complexes were only lysed by HLA-B7 positive CMV-specific CTL, whereas HLA-A2/CMV complex targeted HLA-A2 positive B-CLL cells were unaffected by HLA-B7 positive CMV specific CTL, proving HLA restriction of the killing.. Furthermore, CD20-HLA/CMV complex coated B-CLL cells induce both proliferation and cytokine production (interferon γ, tumor necrosis factor α, and macrophage inflammatory protein-1 β) in CMV-specific CD8+ T cells. Thus, CD20-HLA/CMV complexes elicit both immune activation and direct cytotoxicity towards B-CLL cells. The findings of our study constitute a necessary step towards possible application of CD20-HLA/CMV complexes for immunotherapy of B cell malignancies. It is obvious that this recently recognized capacity to redirect existing antiviral immunity towards tumor cells has a utility in cancer immunotherapy far beyond CMV and B-CLL.

scholarly journals A role for CCR4 in development of mature circulating cutaneous T helper memory cell populations

2005 ◽  
Vol 201 (7) ◽  
pp. 1045-1051 ◽  
Author(s):  
Espen S. Baekkevold ◽  
Marc-André Wurbel ◽  
Pia Kivisäkk ◽  
Clare M. Wain ◽  
Christine A. Power ◽  
...  
Keyword(s):  
T Cells ◽  
Memory Cell ◽  
Interferon Γ ◽  
Interleukin 4 ◽  
Th2 Cells ◽  
T Helper ◽  
Th Cells ◽  
Selectin Ligand ◽  
Rag 1 ◽  
Chemokine Receptor Ccr4

Expression of the chemokine receptor CCR4 is strongly associated with trafficking of specialized cutaneous memory T helper (Th) lymphocytes to the skin. However, it is unknown whether CCR4 itself participates in the development of cutaneous Th populations. We have addressed this issue via competitive bone marrow (BM) reconstitution assays; equal numbers of BM cells from CCR4+/+ and CCR4−/− donors were allowed to develop side-by-side within RAG-1−/− hosts. Cells from both donor types developed equally well into B cells, naive CD8 T cells, naive CD4 T cells, interferon-γ+ Th1 cells, and interleukin-4+ Th2 cells. In marked contrast, circulating cutaneous memory Th cells (i.e., E-selectin ligand+ [E-lig+]) were more than fourfold more likely to be derived from CCR4+/+ donors than from CCR4−/− donors. Most of this effect resides within the CD103+ subset of the E-lig+ Th population, in which donor CCR4+/+ cells can outnumber CCR4−/− cells by &gt;12-fold. No similar effect was observed for α4β7+ intestinal memory Th cells or CD103+/E-lig− Th cells. We conclude that CCR4 expression provides a competitive advantage to cutaneous Th cells, either by participating in their development from naive Th cells, or by preferentially maintaining them within the memory population over time.

Fluorescent-activated cell-sorting analysis of intracellular interferon-γ and interleukin-4 in fresh and frozen human peripheral blood T-helper cells

2005 ◽  
Vol 13 (4) ◽  
pp. 441-449 ◽  
Author(s):  
Ruhangiz T. Kilani ◽  
Megan Delehanty ◽  
Heather A. Shankowsky ◽  
Aziz Ghahary ◽  
Paul Scott ◽  
...  
Keyword(s):  
Cell Sorting ◽  
Peripheral Blood ◽  
T Helper Cells ◽  
Human Peripheral Blood ◽  
Interferon Γ ◽  
Interleukin 4 ◽  
T Helper ◽  
Helper Cells

scholarly journals Human Monocyte–Derived Dendritic Cells Induce Naive T Cell Differentiation into T Helper Cell Type 2 (Th2) or Th1/Th2 Effectors

2000 ◽  
Vol 192 (3) ◽  
pp. 405-412 ◽  
Author(s):  
Hiroyuki Tanaka ◽  
Christian E. Demeure ◽  
Manuel Rubio ◽  
Guy Delespesse ◽  
Marika Sarfati
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Human Monocyte ◽  
Cd40 Ligand ◽  
Interferon Γ ◽  
Lymphoid Tissues ◽  
T Helper ◽  
Ligand Interactions ◽  
Helper Cell Type ◽  
Th2 Differentiation

The subset of dendritic cells (DCs) and the nature of the signal inducing DC maturation determine the capacity of DCs to generate polarized immune responses. In this study, we show that the ability of human monocyte-derived DCs (myeloid DC1) to promote T helper type 1 (Th1) or Th2 differentiation was also found to be critically dependent on stimulator/responder ratio. At a low ratio (1:300), mature DCs that have been differentiated after inflammatory (Staphylococcus aureus Cowan 1 or lipopolysaccharide) or T cell–dependent (CD40 ligand) stimulation induced naive T cells to become Th2 (interleukin [IL]-4+, IL-5+, interferon γ) effectors. Th2 differentiation was dependent on B7–CD28 costimulation and enhanced by OX40–OX40 ligand interactions. However, high DC/T cell ratio (1:4) favored a mixed Th1/Th2 cell development. Thus, the fact that the same DC lineage stimulates polarized Th1 or Th2 responses may be relevant since it allows the antigen-presenting cells to initiate an appropriate response for the signal received at the peripheral sites. Controlling the number and the rate of DC migration to the T cell areas in lymphoid tissues may be important for the therapeutic use of DCs.

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