STAT1 in Peripheral Tissue Differentially Regulates Homing of Antigen-Specific Th1 and Th2 Cells

Mikhak, Zamaneh; Fleming, Carolyn M.; Medoff, Benjamin D.; Thomas, Seddon Y.; Tager, Andrew M.; Campanella, Gabriele; Luster, Andrew D.

doi:10.4049/jimmunol.176.8.4959

Cited by 69 publications

(60 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…With Th1-type inflammation, production of STAT1-inducible chemokines leads to recruitment of Th1 and effector CD8 T cells through the cognate Th1-associated chemokine receptors, CCR5, CXCR3, and CXCR6 (8). However, with Th2-type inflammation, production of STAT6-inducible chemokines leads to recruitment of Th2 cells through the cognate Th2-associated chemokine receptors, CCR3, CCR4, and CCR8 (9).…”

mentioning

confidence: 98%

Multiple Chemokine Receptors, Including CCR6 and CXCR3, Regulate Antigen-Induced T Cell Homing to the Human Asthmatic Airway

Thomas

Banerji

Medoff

et al. 2007

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

Human allergic asthma is a chronic inflammatory disease of the airways thought to be driven by allergen-specific Th2 cells, which are recruited into the lung in response to inhaled allergen. To identify chemoattractant receptors that control this homing pattern, we used endobronchial segmental allergen challenge in human atopic asthmatics to define the pattern of chemoattractant receptor expression on recruited T cells as well as the numbers of recruited CD1d-restricted NKT cells and levels of chemokines in the bronchoalveolar (BAL) fluid. CD1d-restricted NKT cells comprised only a small minority of BAL T cells before or after Ag challenge. BAL T cells were enriched in their expression of specific chemoattractant receptors compared with peripheral blood T cells prechallenge, including CCR5, CCR6, CXCR3, CXCR4, and BLT1. Surprisingly, following segmental allergen challenge, no chemoattractant receptor was specifically increased. However, CCR6 and CXCR3, which were expressed on virtually all CD4+ BAL T cells prechallenge, were markedly decreased on all recruited BAL T cells following Ag challenge, suggesting that these receptors were internalized following encounter with ligand in the airway. Our data therefore suggests a role for CCR6 and CXCR3, in conjunction with other chemoattractant receptors, in the recruitment of inflammatory T cells into the BAL during the allergic asthmatic response.

show abstract

mentioning

confidence: 98%

Multiple Chemokine Receptors, Including CCR6 and CXCR3, Regulate Antigen-Induced T Cell Homing to the Human Asthmatic Airway

Thomas

Banerji

Medoff

et al. 2007

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

show abstract

“…In STAT1-deficient mice, adoptively transferred Ag-specific Th1 cells failed to home to the airway in response to local allergen challenge. This failure to home was most likely due to the defect in Ag-induced expression of CXCL9 and CXCL10 in the airway, because intranasal administration of CXCL10 restored trafficking of Th1 cells in STAT1 knockout mice (12). Similarly, STAT6-deficient mice failed to express CCL17 and CCL22 and did not support trafficking of Th2 cells (12,13).…”

mentioning

confidence: 99%

“…This failure to home was most likely due to the defect in Ag-induced expression of CXCL9 and CXCL10 in the airway, because intranasal administration of CXCL10 restored trafficking of Th1 cells in STAT1 knockout mice (12). Similarly, STAT6-deficient mice failed to express CCL17 and CCL22 and did not support trafficking of Th2 cells (12,13). These studies provide further in vivo evidence for differential homing of Th1 and Th2 cells and suggest a link between STAT1 and induction of Th1-associated chemokines in comparison with STAT6 and Th2-associated chemokines.…”

mentioning

confidence: 99%

“…CCL17 and CCL22 are typically induced by IL-4 (or IL-13) via a STAT6-mediated pathway, whereas CXCL9 and CXCL10 are secreted in response to IFN-␥ via a STAT1-mediated pathway (11). A critical role for STAT1 and STAT6 in differential trafficking of Th1 and Th2 cells to the lung has been demonstrated in mice (12,13). In STAT1-deficient mice, adoptively transferred Ag-specific Th1 cells failed to home to the airway in response to local allergen challenge.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Generation of Th1 and Th2 Chemokines by Human Eosinophils: Evidence for a Critical Role of TNF-α

Liu

Bates

Jarjour

et al. 2007

The Journal of Immunology

116

102

View full text Add to dashboard Cite

Emerging evidence suggests a role for eosinophils in immune regulation of T cells. Thus, we sought to determine whether human eosinophils may exert their effect via differential generation of Th1 and Th2 chemokines depending on cytokines in their microenvironment and, if so, to establish the conditions under which these chemokines are produced. Eosinophils cultured with TNF-α plus IL-4 had increased mRNA expression and protein secretion of the Th2-type chemokines, CCL17 (thymus and activation-regulated chemokine) and CCL22 (macrophage-derived chemokine). Conversely, the Th1-type chemokines, CXCL9 (monokine induced by IFN-γ) and CXCL10 (IFN-γ-inducible protein-10), were expressed after stimulation with TNF-α plus IFN-γ. Addition of TNF-α appeared to be essential for IFN-γ-induced release of Th1-type chemokines and significantly enhanced IL-4-induced Th2-type chemokines. Inhibition of NF-κB completely blocked the production of both Th1 and Th2 chemokines. Activation of NF-κB, STAT6, and STAT1 was induced in eosinophils by TNF-α, IL-4, and IFN-γ, respectively. However, there was no evidence for enhancement of these signaling events when eosinophils were stimulated with the combination of TNF-α plus IL-4 or TNF-α plus IFN-γ. Thus, independently activated signaling cascades appear to lead to activation of NF-κB, STAT1, and STAT6, which may then cooperate at the promoter level to increase gene transcription. Our data demonstrate that TNF-α is a vital component for eosinophil chemokine generation and that, depending on the cytokines present in their microenvironment, eosinophils can promote either a Th2 or a Th1 immune response, supporting an immunoregulatory role for eosinophils.

show abstract

“…1 Three CXC chemokines, CXCL9, CXCL10, and CXCL11, signal via CXCR3 2 and mediate biologic functions such as cell migration and proliferation. 3 CXCR3 mediates immunity against pathogens by regulating chemotaxis and function of T cells and other leukocytes, [4][5][6][7] however, CXCR3 also contributes to pathogenesis of autoimmune diseases.…”

Section: Introductionmentioning

confidence: 99%

PI3Kgamma (PI3Kγ) is essential for efficient induction of CXCR3 on activated T cells

Barbi

Cummings

Liu

et al. 2008

Blood

View full text Add to dashboard Cite

The gamma isoform of PI3Kinase (PI3K␥) controls leukocyte chemotaxis by participating in GPCR signaling, and by regulating cellular polarization. Here we show that PI3K␥ is required for efficient induction of CXC chemokine receptor 3 (CXCR3) on T cells upon activation. T cells from PI3K␥ IntroductionThe chemokine receptor CXCR3 is expressed on plasmacytoid dendritic cells (pDCs), natural killer (NK) cells, T cells, and microvascular endothelial cells. 1 Three CXC chemokines, CXCL9, CXCL10, and CXCL11, signal via CXCR3 2 and mediate biologic functions such as cell migration and proliferation. 3 CXCR3 mediates immunity against pathogens by regulating chemotaxis and function of T cells and other leukocytes, 4-7 however, CXCR3 also contributes to pathogenesis of autoimmune diseases. [8][9][10][11] Resting T cells express low levels of CXCR3. Upon activation, T cells up-regulate CXCR3 allowing for an increased responsiveness toward its ligands. 12,13 Both IFN-␥ and STAT1 are required for efficient induction of CXCR3 on CD4 ϩ T cells but not CD8 ϩ T cells. 14 The phosphoinositide-3-kinases (PI3Ks) are required for generation of PIP 3 . Class I PI3Ks are dual-specificity lipid and protein kinases that control cell growth, proliferation, survival, adhesion, and motility. These enzymes include class IA (consisting of PI3K␣, PI3K␤, and PI3K␦) and class IB (PI3K␥). 15 Of these, PI3K␥ participates in leukocyte chemotaxis, mast cell degranulation, neutrophil respiratory burst, and TCR-induced T-cell activation. [15][16][17] TCR-induced activation is essential for up-regulation of CXCR3 on T cells, suggesting that PI3K␥ may regulate CXCR3 expression on activated T cells. 12,13 Therefore, we examined the role of PI3K␥ in regulating CXCR3 on T cells. Our findings show that PI3K␥ is critical for efficient induction of CXCR3 on activated T cells. Methods MicePI3K␥ Ϫ/Ϫ C57BL/6 mice were maintained at The Ohio State University. Wild-type C57BL/6 mice were purchased from Harlan (Madison, WI). IRB approval for this study was obtained from The Ohio State University. In vitro stimulation of T cellsCell suspensions were prepared from spleens of WT or PI3K␥ Ϫ/Ϫ mice, and T cells were isolated by immunomagnetic separation. Cells (90%-94% pure) were plated in 24-well plates at 10 6 /mL and stimulated with plate-bound anti-CD3e (3 g/mL) and anti-CD28 (4 g/mL) at 37°C for 48 hours in the absence of PI3K inhibitor. Subsequently, cells were rested in their conditioned media for 24 hours without stimulation either in the presence of PI3K inhibitors (wortmannin, LY294002, or AS-605240) or DMSO as described previously. 12,14 Generation of PI3K␥ siRNA and gene silencingThe Silencer Express Kit (Ambion, Austin, TX) was used to generate PI3K␥ siRNA-expressing vectors. Efficiency of gene silencing was confirmed by measuring PI3K␥ mRNA levels by real-time polymerase chain reaction (PCR). WT C57BL/6 T cells were stimulated with anti-CD3/CD28 for 48 hours and then transfected with PI3K␥ siRNA-expressing vector using a mouse T-cell Nucleofector kit (Ama...

show abstract

STAT1 in Peripheral Tissue Differentially Regulates Homing of Antigen-Specific Th1 and Th2 Cells

Cited by 69 publications

References 48 publications

Multiple Chemokine Receptors, Including CCR6 and CXCR3, Regulate Antigen-Induced T Cell Homing to the Human Asthmatic Airway

Multiple Chemokine Receptors, Including CCR6 and CXCR3, Regulate Antigen-Induced T Cell Homing to the Human Asthmatic Airway

Generation of Th1 and Th2 Chemokines by Human Eosinophils: Evidence for a Critical Role of TNF-α

PI3Kgamma (PI3Kγ) is essential for efficient induction of CXCR3 on activated T cells

Contact Info

Product

Resources

About