scholarly journals Regulation of the Interleukin (IL)-12R β2 Subunit Expression in Developing T Helper 1 (Th1) and Th2 Cells

1997 ◽  
Vol 185 (5) ◽  
pp. 817-824 ◽  
Author(s):  
Susanne J. Szabo ◽  
Anand S. Dighe ◽  
Ueli Gubler ◽  
Kenneth M. Murphy
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Th2 Cells ◽  
T Helper ◽  
T Helper 1 ◽  
Selective Loss ◽  
Th Cell ◽  
Subunit Expression ◽  
Ifn Γ

The developmental commitment to a T helper 1 (Th1)- or Th2-type response can significantly influence host immunity to pathogens. Extinction of the IL-12 signaling pathway during early Th2 development provides a mechanism that allows stable phenotype commitment. In this report we demonstrate that extinction of IL-12 signaling in early Th2 cells results from a selective loss of IL-12 receptor (IL-12R) β2 subunit expression. To determine the basis for this selective loss, we examined IL-12R β2 subunit expression during Th cell development in response to T cell treatment with different cytokines. IL-12R β2 is not expressed by naive resting CD4+ T cells, but is induced upon antigen activation through the T cell receptor. Importantly, IL-4 and IFN-γ were found to significantly modify IL-12 receptor β2 expression after T cell activation. IL-4 inhibited IL-12R β2 expression leading to the loss of IL-12 signaling, providing an important point of regulation to promote commitment to the Th2 pathway. IFN-γ treatment of early developing Th2 cells maintained IL-12R β2 expression and restored the ability of these cells to functionally respond to IL-12, but did not directly inhibit IL-4 or induce IFN-γ production. Thus, IFN-γ may prevent early Th cells from premature commitment to the Th2 pathway. Controlling the expression of the IL-12R β2 subunit could be an important therapeutic target for the redirection of ongoing Th cell responses.

scholarly journals Modulation of Murine Lyme Borreliosis by Interruption of the B7/CD28 T-Cell Costimulatory Pathway

1998 ◽  
Vol 66 (1) ◽  
pp. 266-271 ◽  
Author(s):  
Marie-Claude Shanafelt ◽  
Insoo Kang ◽  
Stephen W. Barthold ◽  
Linda K. Bockenstedt
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lyme Borreliosis ◽  
T Cell Activation ◽  
Cell Activation ◽  
Interleukin 4 ◽  
Th2 Cells ◽  
Th Cell ◽  
Ifn Γ ◽  
Costimulatory Pathway

ABSTRACT Recent studies have implicated cytokines associated with Th2 cells in the genetic resistance to murine Lyme borreliosis. Because the B7/CD28 costimulatory pathway has been shown to influence the differentiation of Th-cell subsets, we investigated the contribution of the B7 molecules CD80 and CD86 to the Th2 cytokine profile and development of arthritis in BALB/c mice infected with Borrelia burgdorferi. Effective blockade of CD86/CD28 interaction was demonstrated by elimination of interleukin 4 (IL-4) and upregulation of gamma interferon (IFN-γ) responses by B. burgdorferi-specific T cells and by reduction of B. burgdorferi-specific immunoglobulin G. Despite the shift toward a Th1 cytokine pattern, which others have associated with disease susceptibility, the severity of arthritis was unchanged. Moreover, combined CD80/CD86 blockade by using anti-CD80 and anti-CD86 monoclonal antibodies or CTLA-4Ig enhanced IFN-γ production over that seen with CD86 blockade alone, yet augmentation of this Th1-associated cytokine did not enhance disease. These results demonstrate that IL-4 production by T cells in B. burgdorferi-infected BALB/c mice is dependent upon CD86/CD28 interaction and that this cytokine does not contribute significantly to host resistance to the development of arthritis. In addition, combined CD80/CD86 blockade resulted in preferential expansion of IFN-γ-producing T cells in B. burgdorferi infection, suggesting that costimulatory pathways other than B7/CD28 may contribute to T-cell activation during continuous antigen stimulation. These studies may provide insight into the role of the B7/CD28 pathway in other infectious and autoimmune diseases in which deviation of Th cell immune responses occurs and antigen is persistently present.

Blocking ICOS-B7h Signal Can Inhibit the Function of Allogene T Lymphocytes and Decrease the Incidence and Severity of Acute Graft Versus Host Disease in Mouse Model

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4606-4606
Author(s):  
Xiaochen Bao ◽  
Ningxia Song ◽  
Bin Wang ◽  
Jianmin Wang
Keyword(s):  
T Cells ◽  
T Cell ◽  
Fusion Protein ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Recipient Mouse ◽  
T Helper ◽  
Graft Versus Host ◽  
Ifn Γ

Abstract ICOS, a CD28 family member expressed on activated T cells, plays important roles in T cell activation and effector function. Here we report our results of biological activity of ICOS signal on allogeneic T lymphocytes and its effect on acute graft-versus-host disease in mouse model by blocking ICOS-B7h signal with ICOS-Ig fusion protein. Human ICOSIg fusion protein was harvested and purified from supernatant of CHO cells transfected with pSecTag2/Hygro A-ICOS-Ig in our lab. Spleen CD4+ cells from C57BL/6 mouse were stimulated with dendritic cells from BALB/C mouse, with different doses of ICOS-Ig or human-Ig (h-Ig) as controls. Allogeneic aGVHD model was established with lethally irradiated BALB/c recipients receiving allogeneic BM and spleen T cells from C57BL/6 mouse with 100ug ICOS-Ig or h-Ig intropenetoneally 4 times at day 0, day +2, +4 and +6 of transplantation. RESULTS: ICOS-Ig (10ug/mL) significantly inhibited proliferation of CD4+T cells ( P<0.01), decreased the level of TNF-α and elevated level of IL-4 in the supernatants of CD4+ T cells in response to allogeneic mature DCs but had no effect on IFN-γ production; ICOS-Ig blockade elevated apoptosis of splenic CD4+ T cells while had no effect on T cell activation (CD25 expression). ICOS-Ig blockade significantly attenuated the lethal GVHD that occurred in control recipient mice. The average survival time was 13.25±5.87 days for mice in h-Ig group, while 21.42±3.02 days for animals in ICOS-Ig group(p=0.0217). Pathologic evaluation revealed that the liver and intestine of animals in ICOS-Ig group has less lymphocyte infiltration and less architectural disruption than those in control h-Ig group; In vivo, ICOS-Ig had no effect on allogeneic T cells division (h-Ig :98.40±1.32, ICOS-Ig: 97.69±2.19 by FACS analysis of CFSE labeled lymphocyte at day 3 of transplantation) and no effect on the proportion of CD4+/CD8+ (h-Ig: 26.35±0.07, ICOS-Ig: 22.12±0.21), but increased apoptosis of allogeneic CD8+ T cells in GVHD model by FACS analysis of Annexin-V staining lymphocytes at day 10 of transplantation (h-Ig: 20.44±3.83, ICOS-Ig: 22.87±6.94 in CD4+ T cells; h-Ig: 18.73±7.43, ICOS-Ig: 24.03±5.4 in CD8+ T cells). Spleen T cells from mice after transplantation were stimulated by ConA ex vivo, ICOS-Ig group proliferated less than control h-Ig group through cell counting with CCK-8 (h-Ig: 0.86±0.04,ICOS-Ig: 0.69±0.12,P<0.05). (4) ICOS-Ig significantly reduced the secretion of IFN-γ and elevated IL-4 in the serum of recipient mouse. The IFN-γ (pg/mL) detected were 562.27±49.97 in h-Ig group, 49.79±2.81 in ICOS-Ig group; and the IL-4 (pg/mL) detected were 38.819±27.56 in h-Ig group,456.03±69.63 in ICOS-Ig group. (p<0.05). (5)ICOS-Ig significantly reduced the secretion of T-bet and elevated GATA-3 in the spleens of recipient mouse. The T-bet/GATA-3 detected were 1.87±0.65 in h-Ig group, 0.56±0.03 in ICOS-Ig (p=0.03). CONCLUSION: The ICOS-Ig fusion protein had bioactivity of inhibition of T cell proliferation and alternated the polarization of T helper cells; It promoted the apoptosis of allo-reactive T cells from donor animals but had no effect on the activation of allo-reactive CD4+T cells; ICOS-Ig blockade can prevent aGVHD through attenuating the function of the allo-reactive T cells, elevating apoptosis of allo-reactive T cells and alternating the polarization of T helper cells.

scholarly journals Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction

2006 ◽  
Vol 203 (12) ◽  
pp. 2673-2682 ◽  
Author(s):  
Kojiro Sato ◽  
Ayako Suematsu ◽  
Kazuo Okamoto ◽  
Akira Yamaguchi ◽  
Yasuyuki Morishita ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Subset ◽  
Bone Destruction ◽  
Autoimmune Arthritis ◽  
Th Cell ◽  
Ifn Γ

In autoimmune arthritis, traditionally classified as a T helper (Th) type 1 disease, the activation of T cells results in bone destruction mediated by osteoclasts, but how T cells enhance osteoclastogenesis despite the anti-osteoclastogenic effect of interferon (IFN)-γ remains to be elucidated. Here, we examine the effect of various Th cell subsets on osteoclastogenesis and identify Th17, a specialized inflammatory subset, as an osteoclastogenic Th cell subset that links T cell activation and bone resorption. The interleukin (IL)-23–IL-17 axis, rather than the IL-12–IFN-γ axis, is critical not only for the onset phase, but also for the bone destruction phase of autoimmune arthritis. Thus, Th17 is a powerful therapeutic target for the bone destruction associated with T cell activation.

scholarly journals CCL19 enhances CD8+ T-cell responses and accelerates HBV clearance

2021 ◽  
Author(s):  
Yan Yan ◽  
Wei Zhao ◽  
Wei Liu ◽  
Yan Li ◽  
Xu Wang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Crucial Role ◽  
Cell Activation ◽  
Hbv Infection ◽  
Host Immune System ◽  
Tnf Α ◽  
Ifn Γ ◽  
High Level

Abstract Background Chemokine (C–C motif) ligand 19 (CCL19) is a leukocyte chemoattractant that plays a crucial role in cell trafficking and leukocyte activation. Dysfunctional CD8+ T cells play a crucial role in persistent HBV infection. However, whether HBV can be cleared by CCL19-activated immunity remains unclear. Methods We assessed the effects of CCL19 on the activation of PBMCs in patients with HBV infection. We also examined how CCL19 influences HBV clearance and modulates HBV-responsive T cells in a mouse model of chronic hepatitis B (CHB). In addition, C–C chemokine-receptor type 7 (CCR7) knockdown mice were used to elucidate the underlying mechanism of CCL19/CCR7 axis-induced immune activation. Results From in vitro experiments, we found that CCL19 enhanced the frequencies of Ag-responsive IFN-γ+ CD8+ T cells from patients by approximately twofold, while CCR7 knockdown (LV-shCCR7) and LY294002 partially suppressed IFN-γ secretion. In mice, CCL19 overexpression led to rapid clearance of intrahepatic HBV likely through increased intrahepatic CD8+ T-cell proportion, decreased frequency of PD-1+ CD8+ T cells in blood and compromised suppression of hepatic APCs, with lymphocytes producing a significantly high level of Ag-responsive TNF-α and IFN-γ from CD8+ T cells. In both CCL19 over expressing and CCR7 knockdown (AAV-shCCR7) CHB mice, the frequency of CD8+ T-cell activation-induced cell death (AICD) increased, and a high level of Ag-responsive TNF-α and low levels of CD8+ regulatory T (Treg) cells were observed. Conclusions Findings in this study provide insights into how CCL19/CCR7 axis modulates the host immune system, which may promote the development of immunotherapeutic strategies for HBV treatment by overcoming T-cell tolerance.

scholarly journals TheM. tuberculosisPhosphate-Binding Lipoproteins PstS1 and PstS3 Induce Th1 and Th17 Responses That Are Not Associated with Protection againstM. tuberculosisInfection

2011 ◽  
Vol 2011 ◽  
pp. 1-11 ◽  
Author(s):  
Carla Palma ◽  
Ralf Spallek ◽  
Giovanni Piccaro ◽  
Manuela Pardini ◽  
Fatima Jonas ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Phosphate Binding ◽  
Specific Immunity ◽  
Ifn Γ

TheM. tuberculosisphosphate-binding transporter lipoproteins PstS1 and PstS3 were good immunogens inducing CD8+T-cell activation and both Th1 and Th17 immunity in mice. However, this antigen-specific immunity, even when amplified by administration of the protein with the adjuvant LTK63 or by the DNA priming/protein boosting regimen, was not able to containM. tuberculosisreplication in the lungs of infected mice. The lack of protection might be ascribed with the scarce/absent capacity of PstS1/PstS3 antigens to modulate the IFN-γ response elicited byM. tuberculosisinfection during which, however, PstS1-specific IL-17 secreting cells were generated in both unvaccinated and BCG-vaccinated mice. In spite of a lack of protection by PstS1/PstS3 immunizations, our results do show that PstS1 is able to induce IL-17 response uponM. tuberculosisinfection which is of interest in the study of anti-M. tuberculosisimmunity and as potential immunomodulator in combined vaccines.

scholarly journals A Signal Transducer and Activator of  Transcription (Stat)4-independent Pathway for the Development of  T Helper Type 1 Cells

1998 ◽  
Vol 188 (6) ◽  
pp. 1191-1196 ◽  
Author(s):  
Mark H. Kaplan ◽  
Andrea L. Wurster ◽  
Michael J. Grusby
Keyword(s):  
Delayed Type Hypersensitivity ◽  
Th2 Cells ◽  
Signal Transducer ◽  
T Helper ◽  
Th1 Cell ◽  
Th Cells ◽  
Th Cell ◽  
Ifn Γ

The differentiation of T helper (Th) cells is regulated by members of the signal transducer and activator of transcription (STAT) family of signaling molecules. We have generated mice lacking both Stat4 and Stat6 to examine the ability of Th cells to develop in the absence of these two transcription factors. Stat4, Stat6−/− lymphocytes fail to differentiate into interleukin (IL)-4–secreting Th2 cells. However, in contrast to Stat4−/− lymphocytes, T cells from Stat4, Stat6−/− mice produce significant amounts of interferon (IFN)-γ when activated in vitro. Although Stat4, Stat6−/− lymphocytes produce less IFN-γ than IL-12–stimulated control lymphocytes, equivalent numbers of IFN-γ–secreting cells can be generated from cultures of Stat4, Stat6−/− lymphocytes activated under neutral conditions and control lymphocytes activated under Th1 cell–promoting conditions. Moreover, Stat4, Stat6−/− mice are able to mount an in vivo Th1 cell–mediated delayed-type hypersensitivity response. These results support a model of Th cell differentiation in which the generation of Th2 cells requires Stat6, whereas a Stat4-independent pathway exists for the development of Th1 cells.

scholarly journals Combination Treatment of Topical Imiquimod Plus Anti-PD-1 Antibody Exerts Significantly Potent Antitumor Effect

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 3948
Author(s):  
Kazumasa Oya ◽  
Yoshiyuki Nakamura ◽  
Zhu Zhenjie ◽  
Ryota Tanaka ◽  
Naoko Okiyama ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Combination Therapy ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Antitumor Effect ◽  
Skin Lesions ◽  
Ifn Γ ◽  
Deficient Mice

The exact mechanisms of the imiquimod (IMQ)-induced antitumor effect have not been fully understood. Although both topical IMQ treatment and anti-PD-1 antibody may be used for primary skin lesions or skin metastases of various cancers, the efficacy of each monotherapy for these lesions is insufficient. Using a murine tumor model and human samples, we aimed to elucidate the detailed mechanisms of the IMQ-induced antitumor effect and analyzed the antitumor effect of combination therapy of topical IMQ plus anti-PD-1 antibody. Topical IMQ significantly suppressed the tumor growth of MC38 in wildtype mice. IMQ upregulated interferon γ (IFN-γ) expression in CD8+ T cells in both the lymph nodes and the tumor, and the antitumor effect was abolished in both Rag1-deficient mice and IFN-γ-deficient mice, indicating that IFN-γ produced by CD8+ T cells play a crucial role in the IMQ-induced antitumor effect. IMQ also upregulated PD-1 expression in T cells as well as PD-L1/PD-L2 expression in myeloid cells, suggesting that IMQ induces not only T-cell activation but also T-cell exhaustion by enhanced PD-1 inhibitory signaling. Combination therapy of topical IMQ plus anti-PD-1 antibody exerted a significantly potent antitumor effect when compared with each single therapy, indicating that the combination therapy is a promising therapy for the skin lesions of various cancers.

Experimental silicosis: a shift to a preferential IFN-γ-based Th1 response in thoracic lymph nodes

2000 ◽  
Vol 278 (6) ◽  
pp. L1221-L1230 ◽  
Author(s):  
Holger Garn ◽  
Anke Friedetzky ◽  
Andrea Kirchner ◽  
Ruth Jäger ◽  
Diethard Gemsa
Keyword(s):  
T Cell ◽  
Lymph Nodes ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cytotoxic T Cell ◽  
Mrna Levels ◽  
Ifn Γ

In chronic silicosis, mechanisms leading to lymphocyte activation are still poorly understood, although it is well known that not only the lung but also the draining lymph nodes are affected. In the present study, we investigated T-cell activation by analysis of cytokine expression in the enlarged thoracic lymph nodes of rats 2 mo after an 8-day silica aerosol exposure. In the case of helper T cell (Th) type 1 cytokines, we found a significant increase in interferon (IFN)-γ mRNA expression, whereas interleukin (IL)-2 expression remained unchanged. In contrast, gene transcription for the Th2-type cytokines IL-4 and IL-10 was diminished. In addition, with use of an in vitro lymphocyte-macrophage coculture system, an enhanced IFN-γ and a reduced IL-10 release were shown with cells from silicotic animals. With regard to IFN-γ-inducing cytokines, we observed enhanced IL-12 mRNA levels in vivo, whereas IL-18 gene expression was slightly decreased. These data indicate that a persistent shift toward an IFN-γ-dominated type 1 (Th1/cytotoxic T cell type 1) T-cell reaction pattern occurred within the thoracic lymph nodes of silicotic animals. Thus a mutual activation of lymphocytes and macrophages may maintain the chronic inflammatory changes that characterize silicosis.

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