scholarly journals A Critical Role for OX40 in T Cell–mediated Immunopathology during Lung Viral Infection

2003 ◽  
Vol 198 (8) ◽  
pp. 1237-1242 ◽  
Author(s):  
Ian R. Humphreys ◽  
Gerhard Walzl ◽  
Lorna Edwards ◽  
Aaron Rae ◽  
Sue Hill ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Therapeutic Potential ◽  
Respiratory Infections ◽  
Critical Role ◽  
Activated T Cells ◽  
Virus Clearance ◽  
Immune Mediated ◽  
Antigen Presenting ◽  
Costimulatory Pathway

Respiratory infections are the third leading cause of death worldwide. Illness is caused by pathogen replication and disruption of airway homeostasis by excessive expansion of cell numbers. One strategy to prevent lung immune–mediated damage involves reducing the cellular burden. To date, antiinflammatory strategies have affected both antigen-specific and naive immune repertoires. Here we report a novel form of immune intervention that specifically targets recently activated T cells alone. OX40 (CD134) is absent on naive T cells but up-regulated 1–2 d after antigen activation. OX40–immunoglobulin fusion proteins block the interaction of OX40 with its ligand on antigen-presenting cells and eliminate weight loss and cachexia without preventing virus clearance. Reduced proliferation and enhanced apoptosis of lung cells accompanied the improved clinical phenotype. Manipulation of this late costimulatory pathway has clear therapeutic potential for the treatment of dysregulated lung immune responses.

scholarly journals The importance of the back–signal from T cells into antigen–presenting cells in determining susceptibility to parasites

1997 ◽  
Vol 352 (1359) ◽  
pp. 1327-1330 ◽  
Author(s):  
Brigitte Müller ◽  
Avrion Mitchison
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Activated T Cells ◽  
Ifn Gamma ◽  
Parasite Infections ◽  
Antigen Presenting ◽  
Mhc Class Ii Genes ◽  
Mhc Class Ii Molecules

It has long been known that certain MHC class II genes can dominantly suppress immune responses and so increase susceptibility to parasite infections, but the mechanism has been unclear. Recent work has revealed one way in which this form of suppression may operate through gating by MHC class II molecules of the back–signal from activated T cells into macrophages. The two known suppressive genes of the mouse are expressed in macrophages more extensively than are other class II genes. This is asscociated with suppresion of IL–4 production resulting, we infer, from overproduction in the macrophages of IL–12, the counter–cytokine to IL–4. The lack of IL–4 may itself be immunosuppressive, even for Th2 responses, and excess IL–12 can overinduce the antiproliferative cytokine IFN–gamma. Although this mechanism requires further substantiation, we believe that it offers a reasonable answer to an old conundrum.

scholarly journals Regulatory T-cell: Regulator of Host Defense in Infection

2017 ◽  
Vol 7 (1) ◽  
pp. 9 ◽  
Author(s):  
Mousa Mohammadnia-Afrouzi ◽  
Mehdi Shahbazi ◽  
Sedigheh Baleghi Damavandi ◽  
Ghasem Faghanzadeh Ganji ◽  
Soheil Ebrahimpour
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Immune Responses ◽  
Regulatory T Cell ◽  
Critical Role ◽  
The Body ◽  
Cell Contact ◽  
Infectious Agents ◽  
Activated T Cells

Based on diverse activities and production of several cytokines, T lymphocytes and T helper cells are divided into Th1, Th2, Th17 and regulatory T-cell (T regs) subsets based on diverse activities and production of several cytokines. Infectious agents can escape from host by modulation of immune responses as effector T-cells and Tregs. Thus, regulatory T-cells play a critical role in suppression of immune responses to infectious agents such as viruses, bacteria, parasites and fungi and as well as preserving immune homeostasis. However, regulatory T-cell responses can advantageous for the body by minimizing the tissue-damaging effects. The following subsets of regulatory T-cells have been recognized: natural regulatory Tcells, Th3, Tr1, CD8+ Treg, natural killer like Treg (NKTreg) cells. Among various markers of Treg cells, Forkhead family transcription factor (FOXP3) as an intracellular protein is used for discrimination between activated T reg cells and activated T-cells. FOXP3 has a central role in production, thymocyte differentiation and function of regulatory Tcells. Several mechanisms have been indicated in regulation of T reg cells. As, the suppression of T-cells via regulatory T-cells is either mediated by Cell-cell contact and Immunosuppressive cytokines (TGF-Beta, IL-10) mediated.

scholarly journals Regulatory T Cells Inhibit T Cell Activity by Downregulating CD137 Ligand via CD137 Trogocytosis

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 353
Author(s):  
Khang Luu ◽  
Mugdha Vijay Patwardhan ◽  
Qun Zeng ◽  
Stina L. Wickström ◽  
Andreas Lundqvist ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Immune Responses ◽  
Costimulatory Molecule ◽  
Cell Activity ◽  
Effector T Cells ◽  
Comparable Data ◽  
Activated T Cells ◽  
Evolutionarily Conserved ◽  
Antigen Presenting

CD137 is a costimulatory molecule expressed on activated T cells. CD137 ligand (CD137L) is expressed by antigen presenting cells (APC), which use the CD137—CD137L system to enhance immune responses. It was, therefore, surprising to discover CD137 expression on regulatory T cells (Treg). The function of CD137 in Treg are controversial. While some studies report that CD137 signalling converts Treg to effector T cells (Teff), other studies find that CD137-expressing Treg display a stronger inhibitory activity than CD137- Treg. Here, we describe that CD137 on Treg binds to CD137L on APC, upon which one of the two molecules is transferred via trogocytosis to the other cell, where CD137—CD137L forms a complex that is internalized and deprives APC of the immune-stimulatory CD137L. Truncated forms of CD137 that lack the cytoplasmic domain of CD137 are also able to downregulate CD137L, demonstrating that CD137 signalling is not required. Comparable data have been obtained with human and murine cells, indicating that this mechanism is evolutionarily conserved. These data describe trogocytosis of CD137 and CD137L as a new mechanism employed by Treg to control immune responses by downregulating the immunostimulatory CD137L on APC.

scholarly journals Impairment of Antigen-Presenting Cell Function in Mice Lacking Expression of Ox40 Ligand

2000 ◽  
Vol 191 (2) ◽  
pp. 365-374 ◽  
Author(s):  
Kazuko Murata ◽  
Naoto Ishii ◽  
Hiroshi Takano ◽  
Shigeto Miura ◽  
Lishomwa C. Ndhlovu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Function ◽  
Critical Role ◽  
Costimulatory Molecule ◽  
Activated T Cells ◽  
Antigen Presenting

OX40 expressed on activated T cells is known to be an important costimulatory molecule on T cell activation in vitro. However, the in vivo functional significance of the interaction between OX40 and its ligand, OX40L, is still unclear. To investigate the role of OX40L during in vivo immune responses, we generated OX40L-deficient mice and a blocking anti-OX40L monoclonal antibody, MGP34. OX40L expression was demonstrated on splenic B cells after CD40 and anti-immunoglobulin (Ig)M stimulation, while only CD40 ligation was capable of inducing OX40L on dendritic cells. OX40L-deficient and MGP34-treated mice engendered apparent suppression of the recall reaction of T cells primed with both protein antigens and alloantigens and a significant reduction in keyhole limpet hemocyanin–specific IgG production. The impaired T cell priming was also accompanied by a concomitant reduction of both T helper type 1 (Th1) and Th2 cytokines. Furthermore, antigen-presenting cells (APCs) derived from the mutant mice revealed an impaired intrinsic APC function, demonstrating the importance of OX40L in both the priming and effector phases of T cell activation. Collectively, these results provide convincing evidence that OX40L, expressed on APCs, plays a critical role in antigen-specific T cell responses in vivo.

scholarly journals Distinct Immune Responses in Resistant and Susceptible Strains of Mice during Neurovirulent Alphavirus Encephalomyelitis

2015 ◽  
Vol 89 (16) ◽  
pp. 8280-8291 ◽  
Author(s):  
Kirsten A. Kulcsar ◽  
Victoria K. Baxter ◽  
Rachy Abraham ◽  
Ashley Nelson ◽  
Diane E. Griffin
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Immune Responses ◽  
Genetic Background ◽  
Th17 Cells ◽  
Sindbis Virus ◽  
Direct Result ◽  
Fatal Disease ◽  
Virus Clearance ◽  
Immune Mediated

ABSTRACTSusceptibility to alphavirus encephalomyelitis is dependent on a variety of factors, including the genetic background of the host. Neuroadapted Sindbis virus (NSV) causes uniformly fatal disease in adult C57BL/6 (B6) mice, but adult BALB/c (Bc) mice recover from infection. In B6 mice, fatal encephalomyelitis is immune mediated rather than a direct result of virus infection. To identify the immunological determinants of host susceptibility to fatal NSV-induced encephalomyelitis, we compared virus titers and immune responses in adult B6 and Bc mice infected intranasally with NSV. B6 mice had higher levels of virus replication, higher levels of type I interferon (IFN), and slower virus clearance than did Bc mice. B6 mice had more neuronal apoptosis, more severe neurologic disease, and higher mortality than Bc mice. B6 mice had more infiltration of inflammatory cells and higher levels ofIL1b,IL-6,TNFa,Csf2, andCCL2mRNAs and interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), IFN-γ, and C-C motif ligand 2 (CCL2) protein in brains than Bc mice. However, Bc mice had more brain antibody at day 7 and a higher percentage of CD4+T cells. CD4+T cells in the brains of Bc mice included fewer Th17 cells and more regulatory T cells (Tregs) producing IL-10 than B6 mice, accompanied by higher levels ofIl2andCxcl10mRNAs. In the absence of IL-10, resistant Bc mice became susceptible to fatal encephalomyelitis after NSV infection. These studies demonstrate the importance of the immune response and its regulation in determining host survival during alphavirus encephalomyelitis.IMPORTANCEMosquito-borne alphavirus infections are an important cause of encephalomyelitis in humans. The severity of disease is dependent both on the strain of the virus and on the age and genetic background of the host. A neurovirulent strain of Sindbis virus causes immune-mediated fatal encephalomyelitis in adult C57BL/6 mice but not in BALB/c mice. To determine the host-dependent immunological mechanisms underlying the differences in susceptibility between these two strains of mice, we compared their immune responses to infection. Resistance to fatal disease in BALB/c mice was associated with better antibody responses, more-rapid virus clearance, fewer Th17 cells, and more-potent regulatory T cell responses than occurred in susceptible C57BL/6 mice. In the absence of interleukin-10, a component of the regulatory immune response, resistant mice became susceptible to lethal disease. This study demonstrates the importance of the immune response and its regulation for host survival during alphavirus encephalomyelitis.

Interferon-γ-stimulated marrow stromal cells: a new type of nonhematopoietic antigen-presenting cell

Blood ◽  
2006 ◽  
Vol 107 (6) ◽  
pp. 2570-2577 ◽  
Author(s):  
John Stagg ◽  
Sandra Pommey ◽  
Nicoletta Eliopoulos ◽  
Jacques Galipeau
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Stromal Cells ◽  
Matrix Protein ◽  
Marrow Stromal Cells ◽  
Human Mscs ◽  
Dependent Manner ◽  
Antigen Presenting ◽  
Significant Production

AbstractSeveral studies have demonstrated that marrow stromal cells (MSCs) can suppress allogeneic T-cell responses. However, the effect of MSCs on syngeneic immune responses has been largely overlooked. We describe here that primary MSCs derived from C57BL/6 mice behave as conditional antigen-presenting cells (APCs) and can induce antigen-specific protective immunity. Interferon gamma (IFNγ)-treated C57BL/6 MSCs, but not unstimulated MSCs, cocultured with ovalbumin-specific major histocompatibility (MHC) class II-restricted hybridomas in the presence of soluble ovalbumin-induced significant production of interleukin-2 (IL-2) in an antigen dose-dependent manner (P < .005). IFNγ-treated MSCs could further activate in vitro ovalbumin-specific primary transgenic CD4+ T cells. C57BL/6 MSCs, however, were unable to induce antigen cross-presentation via the MHC class I pathway. When syngeneic mice were immunized intraperitoneally with ovalbumin-pulsed IFNγ-treated MSCs, they developed antigen-specific cytotoxic CD8+ T cells and became fully protected (10 of 10 mice) against ovalbumin-expressing E.G7 tumors. Human MSCs were also studied for antigen-presenting functions. IFNγ-treated DR1-positive human MSCs, but not unstimulated human MSCs, induced significant production of IL-2 when cocultured with DR1-restricted influenza-specific humanized T-cell hybridomas in the presence of purified influenza matrix protein 1. Taken together, our data strongly suggest that MSCs behave as conditional APCs in syngeneic immune responses. (Blood. 2006;107:2570-2577)

scholarly journals A role for CD9 molecules in T cell activation.

1996 ◽  
Vol 184 (2) ◽  
pp. 753-758 ◽  
Author(s):  
X G Tai ◽  
Y Yashiro ◽  
R Abe ◽  
K Toyooka ◽  
C R Wood ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
T Cell Activation ◽  
Cell Activation ◽  
Expression Cloning ◽  
Wild Type ◽  
Almost All ◽  
Antigen Presenting ◽  
Deficient Mice

Costimulation mediated by the CD28 molecule plays an important role in optimal activation of T cells. However, CD28-deficient mice can mount effective T cell-dependent immune responses, suggesting the existence of other costimulatory systems. In a search for other costimulatory molecules on T cells, we have developed a monoclonal antibody (mAb) that can costimulate T cells in the absence of antigen-presenting cells (APC). The molecule recognized by this mAb, 9D3, was found to be expressed on almost all mature T cells and to be a protein of approximately 24 kD molecular mass. By expression cloning, this molecule was identified as CD9, 9D3 (anti-CD9) synergized with suboptimal doses of anti-CD3 mAb in inducing proliferation by virgin T cells. Costimulation was induced by independent ligation of CD3 and CD9, suggesting that colocalization of these two molecules is not required for T cell activation. The costimulation by anti-CD9 was as potent as that by anti-CD28. Moreover, anti-CD9 costimulated in a CD28-independent way because anti-CD9 equally costimulated T cells from the CD28-deficient as well as wild-type mice. Thus, these results indicate that CD9 serves as a molecule on T cells that can deliver a potent CD28-independent costimulatory signal.

scholarly journals The tolerogenic interplay(s) among HLA-G, myeloid APCs, and regulatory cells

Blood ◽  
2011 ◽  
Vol 118 (25) ◽  
pp. 6499-6505 ◽  
Author(s):  
Edgardo D. Carosella ◽  
Silvia Gregori ◽  
Joel LeMaoult
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Immune Responses ◽  
Recent Work ◽  
Large Body ◽  
Regulatory Cells ◽  
Individual Effects ◽  
The Individual ◽  
Key Aspects ◽  
Antigen Presenting

Abstract Myeloid antigen-presenting cells (APCs), regulatory cells, and the HLA-G molecule are involved in modulating immune responses and promoting tolerance. APCs are known to induce regulatory cells and to express HLA-G as well as 2 of its receptors; regulatory T cells can express and act through HLA-G; and HLA-G has been directly involved in the generation of regulatory cells. Thus, interplay(s) among HLA-G, APCs, and regulatory cells can be easily envisaged. However, despite a large body of evidence on the tolerogenic properties of HLA-G, APCs, and regulatory cells, little is known on how these tolerogenic players cooperate. In this review, we first focus on key aspects of the individual relationships between HLA-G, myeloid APCs, and regulatory cells. In its second part, we highlight recent work that gathers individual effects and demonstrates how intertwined the HLA-G/myeloid APCs/regulatory cell relationship is.

Introduction

2004 ◽  
Vol 8 (2_suppl) ◽  
pp. 1-2
Author(s):  
Daniel N. Sauder
Keyword(s):  
T Cells ◽  
Immune System ◽  
Ultraviolet A ◽  
Activated T Cells ◽  
Keratinocyte Proliferation ◽  
Memory T Cell ◽  
Immune Mediated ◽  
Selective Targeting ◽  
Traditional Therapies ◽  
Pathogenic Process

Psoriasis is an immune-mediated skin disease in which T cells initiate and maintain the pathogenic process.1 T cells become activated, migrate into the skin, and induce the keratinocyte proliferation associated with the psoriatic phenotype. The activated T cells that infiltrate the skin express the memory phenotype (CD45RO+).2,3 Both CD4+ and CD8+ memory T-cell subtypes are believed to play a role in the pathogenesis of psoriasis. The effectiveness of many traditional therapies for psoriasis (e.g., cyclosporine, methotrexate, psoralen/ultraviolet A light) can be attributed, at least in part, to the potent immunosuppressive effects of these treatments.4,5 Unfortunately, a lack of selective targeting of the immune system by these therapies may result in treatment-limiting side effects.

scholarly journals Eomes Impedes Durable Response to Tumor Immunotherapy by Inhibiting Stemness, Tissue Residency, and Promoting the Dysfunctional State of Intratumoral CD8+ T Cells

2021 ◽  
Vol 9 ◽  
Author(s):  
Runzi Sun ◽  
Yixian Wu ◽  
Huijun Zhou ◽  
Yanshi Wu ◽  
Zhongzhou Yang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Critical Role ◽  
Cell Subset ◽  
Tumor Immunotherapy ◽  
Genetic Circuit ◽  
Durable Response ◽  
T Cell Immune Responses ◽  
Deficient Mice

Sustaining efficacious T cell-mediated antitumor immune responses in the tumor tissues is the key to the success of cancer immunotherapy. Current strategies leverage altering the signals T cells sense in the tumor microenvironment (TME). Checkpoint inhibitor-based approaches block inhibitory signals such as PD-1 whereas cytokine-based therapies increase the level of immune-stimulatory cytokines such as IL-2. Besides extrinsic signals, the genetic circuit within T cells also participates in determining the nature and trajectory of antitumor immune responses. Here, we showed that efficacy of the IL33-based tumor immunotherapy was greatly enhanced in mice with T cell-specific Eomes deficiency. Mechanistically, we demonstrated that Eomes deficient mice had diminished proportions of exhausted/dysfunctional CD8+ T cells but increased percentages of tissue resident and stem-like CD8+ T cells in the TME. In addition, the IFNγ+TCF1+ CD8+ T cell subset was markedly increased in the Eomes deficient mice. We further demonstrated that Eomes bound directly to the transcription regulatory regions of exhaustion and tissue residency genes. In contrast to its role in inhibiting T cell immune responses at the tumor site, Eomes promoted generation of central memory T cells in the peripheral lymphoid system and memory recall responses against tumor growth at a distal tissue site. Finally, we showed that Eomes deficiency in T cells also resulted in increased efficacy of PD-1-blockade tumor immunotherapy. In all, our study indicates that Eomes plays a critical role in restricting prolonged T cell-mediated antitumor immune responses in the TME whereas promoting adaptive immunity in peripheral lymphoid organs.

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