Structural analysis of the mouse chromosomal gene encoding interleukin 4 which expresses B cell, T cell and mast cell stimulating activities

Dendritic cells (DCs) are bone marrow–derived leukocytes that function as potent antigen presenting cells capable of initiating T cell–dependent responses from quiescent lymphocytes. DC pulsed with tumor-associated antigen (TAA) peptide or protein have recently been demonstrated to elicit antigen-specific protective antitumor immunity in a number of murine models. Transduction of DCs with TAA genes may allow stable, prolonged antigen expression as well as the potential for presentation of multiple, or unidentified, epitopes in association with major histocompatibility complex class I and/or class II molecules. To evaluate the potential efficacy of retrovirally transduced DCs, bone marrow cells harvested from BALB/c mice were transduced with either a model antigen gene encoding β-galactosidase (β-gal) or a control gene encoding rat HER-2/neu (Neu) by coculture with irradiated ecotropic retroviral producer lines. Bone marrow cells were differentiated into DC in vitro using granulocyte/macrophage colony-stimulating factor and interleukin-4. After 7 d in culture, cells were 45–78% double positive for DC phenotypic cell surface markers by FACS® analysis, and DC transduced with β-gal were 41–72% positive for β-gal expression by X-gal staining. In addition, coculture of β-gal transduced DC with a β-gal–specific T cell line (CTLx) resulted in the production of large amounts of interferon-γ, demonstrating that transduced DCs could process and present endogenously expressed β-gal. DC transduced with β-gal and control rat HER-2/neu were then used to treat 3-d lung metastases in mice bearing an experimental murine tumor CT26.CL25, expressing the model antigen, β-gal. Treatment with β-gal–transduced DC significantly reduced the number of pulmonary metastatic nodules compared with treatment with Hank's balanced salt solution or DCs transduced with rat HER-2/neu. In addition, immunization with β-gal–transduced DCs resulted in the generation of antigen-specific cytotoxic T lymphocytes (CTLs), which were significantly more reactive against relevant tumor targets than CTLs generated from mice immunized with DCs pulsed with the Ld-restricted β-gal peptide. The results observed in this rapidly lethal tumor model suggest that DCs transduced with TAA may be a useful treatment modality in tumor immunotherapy.

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Interleukin 4 Reduces Expression of Inhibitory Receptors on B Cells and Abolishes CD22 and FcγRII-mediated B Cell Suppression

Journal of Experimental Medicine ◽

10.1084/jem.20011435 ◽

2002 ◽

Vol 195 (8) ◽

pp. 1079-1085 ◽

Cited By ~ 87

Author(s):

Elizabeth U. Rudge ◽

Antony J. Cutler ◽

Nicholas R. Pritchard ◽

Kenneth G.C. Smith

Keyword(s):

Immune Response ◽

T Cell ◽

B Cells ◽

B Cell ◽

Cell Activation ◽

Interleukin 4 ◽

Cell Immune Response ◽

B Cell Activation ◽

Inhibitory Receptors ◽

T Cell Help

Inhibitory receptors CD22, FcγRII (CD32), CD72, and paired immunoglobulin-like receptor (PIR)-B are critically involved in negatively regulating the B cell immune response and in preventing autoimmunity. Here we show that interleukin 4 (IL-4) reduces expression of all four on activated B cells at the level of messenger RNA and protein. This reduced expression is dependent on continuous exposure to IL-4 and is mediated through Stat6. Coligation of FcγRII to the B cell receptor (BCR) via intact IgG increases the B cell activation threshold and suppresses antigen presentation. IL-4 completely abolishes these negative regulatory effects of FcγRII. CD22 coligation with the BCR also suppresses activation — this suppression too is abolished by IL-4. Thus, IL-4 is likely to enhance the B cell immune response by releasing B cells from inhibitory receptor suppression. By this coordinate reduction in expression of inhibitory receptors, and release from CD22 and FcγRII-mediated inhibition, IL-4 is likely to play a role in T cell help of B cells and the development of T helper cell type 2 responses. Conversely, B cell activation in the absence of IL-4 would be more difficult to achieve, contributing to the maintenance of B cell tolerance in the absence of T cell help.

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B-T cell interactions modulate inhibitory effects of interleukin-4 on human B cell proliferation

European Journal of Immunology ◽

10.1002/eji.1830240233 ◽

1994 ◽

Vol 24 (2) ◽

pp. 480-484

Author(s):

Joelle Taieb ◽

Marie-Thérese Auffredou ◽

Aimé Vazquez

Keyword(s):

Cell Proliferation ◽

T Cell ◽

B Cell ◽

Cell Interactions ◽

Interleukin 4 ◽

Inhibitory Effects ◽

Human B Cell

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Isolation and characterization of a mouse interleukin cDNA clone that expresses B-cell stimulatory factor 1 activities and T-cell- and mast-cell-stimulating activities.

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.83.7.2061 ◽

1986 ◽

Vol 83 (7) ◽

pp. 2061-2065 ◽

Cited By ~ 292

Author(s):

F. Lee ◽

T. Yokota ◽

T. Otsuka ◽

P. Meyerson ◽

D. Villaret ◽

...

Keyword(s):

Mast Cell ◽

T Cell ◽

B Cell ◽

Cdna Clone ◽

Isolation And Characterization ◽

Stimulatory Factor

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A Framework of All Discovered Immunological Pathways and Their Roles for Four Specific Types of Pathogens and Hypersensitivities

10.1101/006965 ◽

2014 ◽

Cited By ~ 1

Author(s):

Wan-Chung Hu

Keyword(s):

Mast Cell ◽

T Cell ◽

Natural Killer Cell ◽

B Cell ◽

Natural Killer ◽

Killer Cell ◽

Cd8 T Cell ◽

Cd4 T Cell ◽

Delayed Type Hypersensitivity ◽

Inkt Cells

AbstractTfh initiates four eradicable immunities. Tfh includes FDC, LTi, IL21 CD4 T cell, and IgG/M B cell. Treg initiates four tolerable immunities. Treg includes DCreg, ILCreg, TGFβ CD4 T cell, and IgA B cell. TH1/TH1-like is immunity for intracellular bacteria/protozoa and type 4 delayed type hypersensitivity. TH1 includes M1 macrophage, mDC2, Tc1 CD8 T cell, IFNg CD4 T cell, ILC1, iNKT1, and IgG3 B cell. TH1-like includes M2 macrophage, ILC1, suppressive CD8 T cell, IFNg/TGFβ CD4 T cell, regulatory iNKT cells, and IgA1 B cell. TH2/TH9 is immunity for helminths and type1 IgE mediated hypersensitivity. TH2 includes iEOS eosinophil, Langerhans cell, basophil/MCt mast cell, IL-4 CD4 T cell, ILC2, iNKT2, and IgE/IgG4 B cell. TH9 includes rEOS eosinophil, basophils/mast cell MCct, IL-9 CD4 T cell, ILC2, regulatory iNKT cells, and IgA2 B cell. TH22/TH17 is immunity for extracellular bacteria/fungi and type 3 immune complex hypersensitivity. TH22 includes N1 neutrophils, mDC1, IL-22 CD4 T cell, ILC3(NCR+), iNKT17, and IgG2 B cell. TH17 includes N2 neutrophils, IL-17 CD4 T cell, regulatory iNKT cells, ILC3(NCR−), and IgA2 B cell. THαβ/TH3 is immunity for viruses and type 2 antibody dependent cytotoxic hypersensitivity. THαβ includes NK1 natural killer cell, pDC, Tc2 CD8 T cell, IL10 CD4 T cell, ILC10, iNKT10, and IgG1 B cell. TH3 includes NK2 natural killer cell, suppressive CD8 T cell, ILC10, IL-10/TGFβ CD4 T cell, regulatory iNKT cells, and IgA1 B cell.Summary sentenceThe summarized framework of host immunities to explain their relations to specific pathogens and hypersensitivities

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Interleukin 4 production by CD4+ T cells from allergic individuals is modulated by antigen concentration and antigen-presenting cell type.

Journal of Experimental Medicine ◽

10.1084/jem.181.3.1081 ◽

1995 ◽

Vol 181 (3) ◽

pp. 1081-1089 ◽

Cited By ~ 169

Author(s):

H Secrist ◽

R H DeKruyff ◽

D T Umetsu

Keyword(s):

Cell Proliferation ◽

T Cells ◽

T Cell ◽

B Cell ◽

Cd4 T Cells ◽

Cd4 T Cell ◽

Interleukin 4 ◽

T Cell Proliferation ◽

High Concentrations ◽

Antigen Presenting

We have previously shown that CD4+ T cells from allergic individuals are predisposed to produce interleukin (IL)-4 in response to allergens, and that allergen immunotherapy greatly reduced IL-4 production in an allergen-specific fashion. The mechanism that results in the reduction of IL-4 synthesis in treated individuals is unknown, but because clinical improvement during immunotherapy is associated with the administration of the highest doses of allergen, we hypothesized that high concentration of allergen results in the downregulation of IL-4 synthesis in CD4+ T cells. In this report, we demonstrated that CD4+ T cells from allergic donors produced high levels of IL-4 when stimulated with low concentrations of allergen (0.003-0.01 micrograms/ml), particularly when B cell-enriched populations presented the antigen. In contrast, the same responding CD4+ T cell population produced little IL-4 when stimulated with high concentrations of allergen (10-30 micrograms/ml), especially when monocytes were used as antigen-presenting cells (APC). The quantity of IL-4 produced was also found to be inversely related to the extent of proliferation of the CD4+ T cells in response to allergen/antigen; maximal proliferation of CD4+ T cells occurred in response to high concentrations of antigen when IL-4 production was minimal. Antigen presentation by B cell-enriched populations, instead of monocytes, induced less CD4+ T cell proliferation, but induced much greater IL-4 synthesis. Moreover, the addition of increasing numbers of APC (either B cells or monocytes) to cultures containing a constant number of responder T cells resulted in increased T cell proliferation and decreased IL-4 production. These results indicate that the circumstances under which memory T cells are activated, as well as the strength of the proliferative signal to T cells, greatly affect the quantity of IL-4 produced. Thus, our observations that the cytokine profile of allergen-specific memory CD4+ T cells can indeed be modulated by the antigen dose and APC type suggest that methods that preferentially enhance allergen uptake by monocytes and that enhance T cell proliferation will improve the clinical efficacy of immunotherapy in the treatment of allergic disease.

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T-Cell Protein Tyrosine Phosphatase, Distinctively Expressed in Activated-B-Cell-Like Diffuse Large B-Cell Lymphomas, Is the Nuclear Phosphatase of STAT6

Molecular and Cellular Biology ◽

10.1128/mcb.01234-06 ◽

2007 ◽

Vol 27 (6) ◽

pp. 2166-2179 ◽

Cited By ~ 58

Author(s):

Xiaoqing Lu ◽

Jun Chen ◽

R. Tedjo Sasmono ◽

Eric D. Hsi ◽

Kristopher A. Sarosiek ◽

...

Keyword(s):

T Cell ◽

B Cell ◽

Tyrosine Phosphatase ◽

Protein Tyrosine Phosphatases ◽

Interleukin 4 ◽

Cell Protein ◽

B Cell Lymphomas ◽

Protein Tyrosine ◽

Protein Levels ◽

Large B Cell

ABSTRACTDiffuse large B-cell lymphomas (DLBCLs) consist of clinically distinct subtypes: germinal center B-cell (GCB)-like and activated-B-cell (ABC)-like tumors, characterized by long and short survival, respectively. We reported distinct interleukin 4 (IL-4) responsiveness and STAT6 signaling in these DLBCL subtypes. Increased nuclear dephosphorylation of phospho-STAT6 (pSTAT6) was observed in ABC-like tumors, which exhibited a different expression profile of protein tyrosine phosphatases (PTPs). Among the differentially expressed PTPs, only T-cell PTP (TCPTP) localizes to the nucleus. Herein, we report that the elevated expression of TCPTP in ABC- versus GCB-like DLBCL tumors is not due to the distinct ontogeny of these neoplasms but rather may be an acquired feature of the tumors. Moreover, we report that STAT6 may serve as a physiological nuclear substrate for TCPTP. We demonstrate interactions between endogenous TCPTP and STAT6 and delineate the domains responsible for the interaction. Overexpression of TCPTP ameliorates IL-4-induced STAT6 phosphorylation and associated gene transcription, whereas knockdown of endogenous TCPTP results in increased IL-4-induced STAT6 signaling. Moreover, we report that TCPTP protein levels may be increased in response to IL-4 and that TCPTP may serve in a negative feedback loop for the suppression of IL-4-induced signaling. Taken together, these results identify TCPTP as a physiological regulator of STAT6 phosphorylation and suggest that specific increases in TCPTP expression in ABC-like DLBCLs may contribute to the different biological characteristics of these tumors.

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