Ectopic expression of IL-5 identifies an additional CD4+T cell mechanism of airway eosinophil recruitment

2002 ◽  
Vol 282 (1) ◽  
pp. L99-L108 ◽  
Author(s):  
Jeffrey R. Crosby ◽  
H. H. Shen ◽  
M. T. Borchers ◽  
J. P. Justice ◽  
T. Ansay ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Inflammatory Responses ◽  
Gene Knockout ◽  
Critical Role ◽  
Ectopic Expression ◽  
Constitutive Expression ◽  
Lung Epithelium ◽  
Eosinophil Recruitment ◽  
Airway Lumen

CD4+T cells have a critical role in the development of allergic pulmonary inflammation, including the recruitment of eosinophils to the airway lumen and interstitium. The expression of interleukin (IL)-5 by CD4+cells has, in particular, often been lionized as the central link between allergic inflammation and the concomitant expansion or recruitment of eosinophils. The mechanism(s) by which CD4+T cells mediates eosinophil recruitment was assessed with gene knockout mice deficient for T cells or T cell subtypes and a unique IL-5 transgenic mouse (line NJ.1726) that constitutively overexpresses this cytokine in the lung epithelium. Pulmonary IL-5 expression is significantly attenuated in T cell- and CD4+but not CD8+cell-deficient animals, suggesting an obvious explanation for the lack of eosinophils in the lungs of T cell-deficient and CD4(−/−) mice. However, although the constitutive expression of IL-5 in the lung epithelium of NJ.1726 mice elicited an eosinophilia in the airway lumen of both naive and ovalbumin-treated mice, in the absence of CD4+cells, allergen-mediated eosinophil recruitment to the bronchoalveolar lavage fluid was abolished. Moreover, intranasal instillation of the potent eosinophil-specific chemokine eotaxin-2 was incapable of eliciting eosinophil recruitment in naive and ovalbumin-treated NJ.1726 CD4(−/−) mice, suggesting that eosinophil trafficking during allergic inflammatory responses is a consequence of a CD4+cell-mediated event(s) in addition to IL-5 expression and the establishment of a pulmonary chemokine gradient.

scholarly journals Early Induction of Interleukin-10 Limits Antigen-Specific CD4+T Cell Expansion, Function, and Secondary Recall Responses during Persistent Phagosomal Infection

2014 ◽  
Vol 82 (10) ◽  
pp. 4092-4103 ◽  
Author(s):  
Abinav Kumar Singh ◽  
Nagaraja R. Thirumalapura
Keyword(s):  
T Cells ◽  
T Cell ◽  
Functional Status ◽  
Persistent Infection ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Interleukin 10 ◽  
Host Cells ◽  
Content Type ◽  
Ifn Γ

ABSTRACTDiverse pathogens have evolved to survive and replicate in the endosomes or phagosomes of the host cells and establish persistent infection. Ehrlichiae are Gram-negative, intracellular bacteria that are transmitted by ticks. Ehrlichiae reside in the endosomes of the host phagocytic or endothelial cells and establish persistent infection in their vertebrate reservoir hosts. CD4+T cells play a critical role in protection against phagosomal infections. In the present study, we investigated the expansion, maintenance, and functional status of antigen-specific CD4+T cells during persistentEhrlichia murisinfection in wild-type and interleukin-10 (IL-10)-deficient mice. Our study indicated that early induction of IL-10 led to reduced inflammatory responses and impaired bacterial clearance during persistentEhrlichiainfection. Notably, we demonstrated that the functional production of gamma interferon (IFN-γ) by antigen-specific CD4+T cells maintained during a persistent phagosomal infection progressively deteriorates. The functional loss of IFN-γ production by antigen-specific CD4+T cells was reversed in the absence of IL-10. Furthermore, we demonstrated that transient blockade of IL-10 receptor during the T cell priming phase early in infection was sufficient to enhance the magnitude and the functional capacity of antigen-specific effector and memory CD4+T cells, which translated into an enhanced recall response. Our findings provide new insights into the functional status of antigen-specific CD4+T cells maintained during persistent phagosomal infection. The study supports the concept that a better understanding of the factors that influence the priming and differentiation of CD4+T cells may provide a basis to induce a protective immune response against persistent infections.

scholarly journals Critical role for perforin and Fas-dependent killing of dendritic cells in the control of inflammation

Blood ◽  
2012 ◽  
Vol 119 (1) ◽  
pp. 127-136 ◽  
Author(s):  
Min Chen ◽  
Kumar Felix ◽  
Jin Wang
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Cell Types ◽  
Activated T Cells ◽  
Ifn Γ

AbstractAfter stimulation of antigen-specific T cells, dendritic cell (DCs) are susceptible to killing by these activated T cells that involve perforin and Fas-dependent mechanisms. Fas-dependent DC apoptosis has been shown to limit DC accumulation and prevent the development of autoimmunity. However, a role for perforin in the maintenance of DC homeostasis for immune regulation remains to be determined. Here we show that perforin deficiency in mice, together with the deletion of Fas in DCs (perforin−/−DC-Fas−/−), led to DC accumulation, uncontrolled T-cell activation, and IFN-γ production by CD8+ T cells, resulting in the development of lethal hemophagocytic lymphohistiocytosis. Consistently, adoptive transfer of Fas−/− DCs induced over-activation and IFN-γ production in perforin−/− CD8+ T cells. Neutralization of IFN-γ prevented the spreading of inflammatory responses to different cell types and protected the survival of perforin−/−DC-Fas−/− mice. Our data suggest that perforin and Fas synergize in the maintenance of DC homeostasis to limit T cell activation, and prevent the initiation of an inflammatory cascade.

scholarly journals Multipotent Adult Progenitor Cells induce Regulatory T cells and promote their Suppressive Phenotype via TGFβ and Monocyte-dependent Mechanisms

2020 ◽  
Author(s):  
Alice Valentin-Torres ◽  
Cora Day ◽  
Jennifer M Taggart ◽  
Nicholas Williams ◽  
Samantha R. Stubblefield ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Progenitor Cells ◽  
Transforming Growth Factor ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Multipotent Adult Progenitor Cells ◽  
Cell Induction ◽  
Suppressive Phenotype

Abstract Background: Dysregulation of the immune system can initiate chronic inflammatory responses that exacerbate disease pathology. Multipotent adult progenitor cells (MAPC® cells), an adult, adherent bone-marrow derived stromal cell, have been observed to promote the resolution of uncontrolled inflammatory responses in a variety of clinical conditions including: acute ischemic stroke, acute myocardial infarction (AMI), graft vs host disease (GvHD), and acute respiratory distress syndrome (ARDS). One of the proposed mechanisms by which MAPC cells modulate immune responses is via the induction of regulatory T cells (Tregs), however, the mechanism(s) involved remains to be fully elucidated. Methods: To examine MAPC cell mediated Treg induction, peripheral mononuclear cells (PBMCs) were co-cultured with MAPC cells at various PBMC: MAPC cell ratios. Treg frequencies and phenotype was determined by flow cytometry. The mechanisms involved in MAPC cell induction of Tregs were assessed using transforming growth factor β (TGF) and indoleamine 2, 3 dioxygenase (IDO) inhibitors. Monocyte involvement in MAPC cell induction of Tregs was also explored.Results: Herein, we demonstrate that, in an in vitro setting, MAPC cells increase Treg frequencies by promoting Treg proliferation and CD4+ T cell differentiation into Tregs. Moreover, MAPC cell-induced Tregs (miTregs) have a more suppressive phenotype characterized by increased expression of CTLA-4, HLA-DR, and PD-L1 and T cell suppression capacity. MAPC cells also promoted Treg activation by inducing CD45RA+ CD45RO+ transitional Tregs. Additionally, we identify TGFβ as an essential factor for Treg induction secreted by MAPC cells. Furthermore, IDO resulted in decreased Treg induction by MAPC cells demonstrating IDO involvement. Our studies also show that CD14+ monocytes play a critical role in Treg induction by MAPC cells. Conclusions Our study describes MAPC cell dependent Treg phenotypic changes and provides evidence of potential mechanisms by which MAPC cells promote Treg differentiation.

scholarly journals Multipotent adult progenitor cells induce regulatory T cells and promote their suppressive phenotype via TGFβ and monocyte-dependent mechanisms

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Alice Valentin-Torres ◽  
Cora Day ◽  
Jennifer M. Taggart ◽  
Nicholas Williams ◽  
Samantha R. Stubblefield ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Progenitor Cells ◽  
Transforming Growth Factor ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Indoleamine 2 ◽  
Multipotent Adult Progenitor Cells ◽  
Suppressive Phenotype

AbstractDysregulation of the immune system can initiate chronic inflammatory responses that exacerbate disease pathology. Multipotent adult progenitor cells (MAPC cells), an adult adherent bone-marrow derived stromal cell, have been observed to promote the resolution of uncontrolled inflammatory responses in a variety of clinical conditions including acute ischemic stroke, acute myocardial infarction (AMI), graft vs host disease (GvHD), and acute respiratory distress syndrome (ARDS). One of the proposed mechanisms by which MAPC cells modulate immune responses is via the induction of regulatory T cells (Tregs), however, the mechanism(s) involved remains to be fully elucidated. Herein, we demonstrate that, in an in vitro setting, MAPC cells increase Treg frequencies by promoting Treg proliferation and CD4+ T cell differentiation into Tregs. Moreover, MAPC cell-induced Tregs (miTregs) have a more suppressive phenotype characterized by increased expression of CTLA-4, HLA-DR, and PD-L1 and T cell suppression capacity. MAPC cells also promoted Treg activation by inducing CD45RA+ CD45RO+ transitional Tregs. Additionally, we identify transforming growth factor beta (TGFβ) as an essential factor for Treg induction secreted by MAPC cells. Furthermore, inhibition of indoleamine 2, 3-dioxygenase (IDO) resulted in decreased Treg induction by MAPC cells demonstrating IDO involvement. Our studies also show that CD14+ monocytes play a critical role in Treg induction by MAPC cells. Our study describes MAPC cell dependent Treg phenotypic changes and provides evidence of potential mechanisms by which MAPC cells promote Treg differentiation.

scholarly journals Identification of a Novel Alternatively Spliced Form of Inflammatory Regulator SWAP-70-Like Adapter of T Cells

2017 ◽  
Vol 2017 ◽  
pp. 1-10 ◽  
Author(s):  
Marie Hashimoto ◽  
Jun-ichi Nagao ◽  
Shojiro Ikezaki ◽  
Sonoko Tasaki ◽  
Ken-ichi Arita-Morioka ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Inflammatory Responses ◽  
Ectopic Expression ◽  
Allergic Inflammation ◽  
Small Gtpases ◽  
Th2 Cells ◽  
Nucleotide Exchange ◽  
Alternatively Spliced

Activation of naive CD4+ T cells results in the development of several distinct subsets of effector Th cells, including Th2 cells that play a pivotal role in allergic inflammation and helminthic infections. SWAP-70-like adapter of T cells (SLAT), also known as Def6 or IBP, is a guanine nucleotide exchange factor for small GTPases, which regulates CD4+ T cell inflammatory responses by controlling Ca2+/NFAT signaling. In this study, we have identified a novel alternatively spliced isoform of SLAT, named SLAT2, which lacks the region encoded by exons 2–7 of the Def6 gene. SLAT2 was selectively expressed in differentiated Th2 cells after the second round of in vitro stimulation, but not in differentiated Th1, Th17, or regulatory T (Treg) cells. Functional assays revealed that SLAT2 shared with SLAT the ability to enhance T cell receptor- (TCR-) mediated activation of NFAT and production of IL-4 but was unable to enhance TCR-induced adhesion to ICAM-1. Ectopic expression of SLAT2 or SLAT in Jurkat T cells resulted in the expression of distinct forms of filopodia, namely, short versus long ones, respectively. These results demonstrate that modulating either SLAT2 or SLAT protein expression could play critical roles in cytokine production and actin reorganization during inflammatory immune responses.

IGF-1 down-regulates IFN-γR2 chain surface expression and desensitizes IFN-γ/STAT-1 signaling in human T lymphocytes

Blood ◽  
2003 ◽  
Vol 102 (8) ◽  
pp. 2933-2939 ◽  
Author(s):  
Paola Bernabei ◽  
Marita Bosticardo ◽  
Giuliana Losana ◽  
Gabriella Regis ◽  
Francesca Di Paola ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Cell Lines ◽  
Critical Role ◽  
Constitutive Expression ◽  
Myeloid Cell ◽  
Surface Expression ◽  
Ifn Γ ◽  
T Cell Lines

Abstract The ability of insulin-like growth factor-1 (IGF-1) to regulate surface expression of the interferon-γ receptor 2 (IFN-γR2) transducing chain and activation of IFN-γ–induced signal transducer and activator of transcription-1 (STAT-1) in human T cells was analyzed. We show that, especially in the absence of serum (which contains IGF-1), IGF-1 down-regulated surface expression of the IFN-γR2 chain and inhibited both IFN-γ–dependent STAT-1 activation and apoptosis in T-cell lines ST4, Jurkat, and Molt-4. IFN-γR2 down-regulation resulted from its enhanced internalization since IGF-1 completely restored the uptake of anti–IFN-γR2 monoclonal antibody (mAb) in serum-deprived T-cell lines. When the interaction between IGF-1 and its receptor was blocked by anti–IGF-1R mAb, enhancement of IFN-γR2 surface expression, STAT-1 activation, and reinstatement of IFN-γ–induced apoptosis were observed. Enhanced expression of IFN-γR2 was also observed in phytohemagglutinin (PHA)–activated T lymphoblasts cultured in the presence of anti–IGF-1R mAb, whereas IGF-1 or anti–IGF-1R mAb did not modify the high IFN-γR2 expression in B and myeloid cell lines. Both IGF-1 and anti–IGF-1R mAb did not modify the constitutive expression of IFN-γR2 mRNA in T cells as well as the high IFN-γR1 binding chain surface expression in T, B, and myeloid cells. These data indicate that IGF-1 plays a critical role in the desensitization of IFN-γ/STAT-1 signaling in T lymphocytes by delivering a signal for IFN-γR2 internalization.

scholarly journals LAT-mediated signaling in CD4+CD25+ regulatory T cell development

2005 ◽  
Vol 203 (1) ◽  
pp. 119-129 ◽  
Author(s):  
Surapong Koonpaew ◽  
Shudan Shen ◽  
Lawrence Flowers ◽  
Weiguo Zhang
Keyword(s):  
T Cells ◽  
T Cell ◽  
Bone Marrow Cells ◽  
Critical Role ◽  
T Cell Development ◽  
Ectopic Expression ◽  
Adaptor Protein ◽  
Foxp3 Expression ◽  
Cell Receptor ◽  
Cell Development

Engagement of the T cell receptor for antigen (TCR) induces formation of signaling complexes mediated through the transmembrane adaptor protein, the linker for activation of T cells (LAT). LAT plays an important role in T cell development, activation, and homeostasis. A knock-in mutation at Tyr136, which is the phospholipase C (PLC)-γ1–binding site in LAT, leads to a severe autoimmune disease in mice. In this study, we show that CD4+CD25+ T reg cells that expressed Foxp3 transcription factor were nearly absent in both thymus and peripheral lymphoid organs of LATY136F mice. This defect was not a result of the autoimmune environment as LATY136F T reg cells also failed to develop in healthy LAT−/− mice that received mixed wild-type and LATY136F bone marrow cells. Moreover, adoptive transfer of normal CD4+CD25+ T reg cells protected neonatal LATY136F mice from developing this disease. These T reg cells effectively controlled expansion of CD4+ T cells in LATY136F mice likely via granzymes and/or TGF-β–mediated suppression. Furthermore, ectopic expression of Foxp3 conferred a suppressive function in LATY136F T cells. Our data indicate that the LAT–PLC-γ1 interaction plays a critical role in Foxp3 expression and the development of CD4+CD25+ T reg cells

scholarly journals Identifying Druglike Inhibitors of Myelin-Reactive T Cells by Phenotypic High-Throughput Screening of a Small-Molecule Library

2007 ◽  
Vol 12 (4) ◽  
pp. 481-489 ◽  
Author(s):  
Christina Rossi ◽  
Deepa Padmanaban ◽  
Jake Ni ◽  
Li-An Yeh ◽  
Marcie A. Glicksman ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Transgenic Mice ◽  
Small Molecule ◽  
High Throughput ◽  
Proinflammatory Cytokines ◽  
High Throughput Screening ◽  
Inflammatory Responses ◽  
Critical Role ◽  
High Throughput Screening Assay

Inflammatory T cells that are reactive to myelin protein components of the CNS play a critical role in the pathogenesis of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). The authors have previously generated mice that predominantly harbor T cells transgenic for a T-cell receptor (TCR) that is specific to the myelin proteolipid protein (PLP) 139-151 and that spontaneously develop MS-like paralysis. T cells from healthy transgenic mice respond to stimulation with PLP139-151 in a highly specific manner by proliferation and secretion of proinflammatory cytokines such as interleukin (IL)—2 and interferon (INF)—γ in vitro. To identify druglike compounds that may inhibit inflammatory T-cell responses, the authors have developed a high-throughput screening assay with primary T cells from PLP TCR transgenic mice. They have screened 41,184 small-molecule compounds that follow Lipinski's rules for their inhibitory activity on the proliferation and secretion of proinflammatory cytokines in PLP-reactive T cells. To this end, the screen identified 6 nontoxic compounds with a molecular weight <500 that inhibited inflammatory responses in PLP-reactive T cells in a concentration-dependent fashion. The identified compounds represent valid leads that may be developed into novel therapeutics for MS that could be administered orally. ( Journal of Biomolecular Screening 2007:481-489)

scholarly journals Local antigen in nonlymphoid tissue promotes resident memory CD8+ T cell formation during viral infection

2016 ◽  
Vol 213 (6) ◽  
pp. 951-966 ◽  
Author(s):  
Tahsin N. Khan ◽  
Jana L. Mooster ◽  
Augustus M. Kilgore ◽  
Jossef F. Osborn ◽  
Jeffrey C. Nolz
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Cd8 T Cell ◽  
Dependent Manner ◽  
Independent Manner ◽  
Tissue Microenvironment ◽  
Nonlymphoid Tissue

Tissue-resident memory (Trm) CD8+ T cells are functionally distinct from their circulating counterparts and are potent mediators of host protection against reinfection. Whether local recognition of antigen in nonlymphoid tissues during infection can impact the formation of Trm populations remains unresolved. Using skin infections with vaccinia virus (VacV)–expressing model antigens, we found that local antigen recognition had a profound impact on Trm formation. Activated CD8+ T cells trafficked to VacV-infected skin in an inflammation-dependent, but antigen-independent, manner. However, after viral clearance, there was a subsequent ∼50-fold increase in Trm formation when antigen was present in the tissue microenvironment. Secondary antigen stimulation in nonlymphoid tissue caused CD8+ T cells to rapidly express CD69 and be retained at the site of infection. Finally, Trm CD8+ T cells that formed during VacV infection in an antigen-dependent manner became potent stimulators of localized antigen-specific inflammatory responses in the skin. Thus, our studies indicate that the presence of antigen in the nonlymphoid tissue microenvironment plays a critical role in the formation of functional Trm CD8+ T cell populations, a finding with relevance for both vaccine design and prevention of inflammatory disorders.

scholarly journals CD40/CD40L contributes to hypercholesterolemia-induced microvascular inflammation

2009 ◽  
Vol 296 (3) ◽  
pp. H689-H697 ◽  
Author(s):  
Karen Y. Stokes ◽  
LeShanna Calahan ◽  
Candiss M. Hamric ◽  
Janice M. Russell ◽  
D. Neil Granger
Keyword(s):  
Oxidative Stress ◽  
T Cells ◽  
T Cell ◽  
Blood Cell ◽  
Cell Function ◽  
Inflammatory Responses ◽  
Microvascular Dysfunction ◽  
Cd40 Ligand ◽  
Scid Mice ◽  
Endothelial Cell Function

Hypercholesterolemia is associated with phenotypic changes in endothelial cell function that lead to a proinflammatory and prothrombogenic state in different segments of the microvasculature. CD40 ligand (CD40L) and its receptor CD40 are ubiquitously expressed and mediate inflammatory responses and platelet activation. The objective of this study was to determine whether CD40/CD40L, in particular T-cell CD40L, contributes to microvascular dysfunction induced by hypercholesterolemia. Intravital microscopy was used to quantify blood cell adhesion in cremasteric postcapillary venules, endothelium-dependent vasodilation responses in arterioles, and microvascular oxidative stress in wild-type (WT) C57BL/6, CD40-deficient (−/−), CD40L−/−, or severe combined immune deficient (SCID) mice placed on a normal (ND) or high-cholesterol (HC) diet for 2 wk. WT-HC mice exhibited an exaggerated leukocyte and platelet recruitment in venules and impaired vasodilation responses in arterioles compared with ND counterparts. A deficiency of CD40, CD40L, or lymphocytes attenuated these responses to HC. The HC phenotype was rescued in CD40L−/− and SCID mice by a transfer of WT T cells. Bone marrow chimeras revealed roles for both vascular- and blood cell-derived CD40 and CD40L in the HC-induced vascular responses. Hypercholesterolemia induced an oxidative stress in both arterioles and venules of WT mice, which was abrogated by either CD40 or CD40L deficiency. The transfer of WT T cells into CD40L−/− mice restored the oxidative stress. These results implicate CD40/CD40L interactions between circulating cells and the vascular wall in both the arteriolar and venular dysfunction elicited by hypercholesterolemia and identify T-cell-associated CD40L as a key mediator of these responses.

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