Allergic humans are hypo‐responsive to CXCR3 chemokines in a Th1 immunity‐promoting loop

Campbell, John D.; Gangur, Venu; Simons, F. Estelle R.; HayGlass, Kent T.

doi:10.1096/fj.02-0908fje

Cited by 84 publications

(67 citation statements)

References 53 publications

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“…It has been postulated that CXCL10 may be relevant in human immune responses not only for its role in the chemotaxis of T cells to inflammatory sites but also for regulating the expression of cytokine synthesis patterns. Furthermore, CXCL10 binding to its receptor was found to act as a costimulus with antigen, resulting in substantially enhanced IFN-␥ production, which inhibited T-cell proliferation (11). In the present study, we also observed a significant increase in IFN-␥ production in L. amazonensis-primed, CXCL10-treated CD4 ϩ T cells (Fig.…”

Section: Discussionsupporting

confidence: 69%

Effects of CXCL10 on Dendritic Cell and CD4⁺T-Cell Functions duringLeishmania amazonensisInfection

Vasquez¹,

Luo²,

Soong

2008

Infect Immun

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Leishmania amazonensis can cause progressive disease in most inbred strains of mice. We have previously reported that treatment with CXCL10 activates macrophage (M⌽) effector function(s) in parasite killing and significantly delays lesion development in susceptible C57BL/6 mice via enhanced gamma interferon (IFN-␥) and interleukin 12 (IL-12) secretion; however, the mechanism underlying this enhanced immunity against L. amazonensis infection remains largely unresolved. In this study, we utilized stationary promastigotes to infect bone marrow-derived dendritic cells (DCs) of C57BL/6 mice and assessed the activation of DC subsets and the capacity of these DC subsets to prime CD4 ؉ T cells in vitro. We found that CXCL10 induced IL-12 p40 production but reduced IL-10 production in uninfected DCs. Yet L. amazonensis-infected DCs produced elevated levels of IL-10 despite CXCL10 treatment. Elimination of endogenous IL-10 led to increased IL-12 p40 production in DCs as well as increased proliferation and IFN-␥ production by in vitro-primed CD4 ؉ T cells. In addition, CXCL10-treated CD4؉ T cells became more responsive to IL-12 via increased expression of the IL-12 receptor ␤ 2 chain and produced elevated levels of IFN-␥. This report indicates the utility of CXCL10 in generating a Th1-favored, proinflammatory response, which is a prerequisite for controlling Leishmania infection.

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Section: Discussionsupporting

confidence: 69%

Effects of CXCL10 on Dendritic Cell and CD4⁺T-Cell Functions duringLeishmania amazonensisInfection

Vasquez¹,

Luo²,

Soong

2008

Infect Immun

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“…CXCL10 secretion potentiates the Th1 immunity-promoting inflammatory loop, driven by the recruited CD4 C T lymphocytes at inflammation sites, supporting T-cell proliferation and IFNg secretion (Campbell et al 2004, Romagnani et al 2004. It is well known that TNFa synergizes with IFNg, modulating a number of different biological effects (Krakauer & Oppenheim 1993).…”

Section: Discussionmentioning

confidence: 99%

Methimazole inhibits CXC chemokine ligand 10 secretion in human thyrocytes

Crescioli

Cosmi²,

Borgogni

et al. 2007

Journal of Endocrinology

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CXC chemokine ligand 10 (CXCL10) plays a pivotal role in the self-perpetuation of the inflammatory processes in patients with autoimmune thyroid disease. Treatment with methimazole (MMI) reduces serum CXCL10 in patients with Graves' disease. In isolated human thyrocytes, tumor necrosis factor (TNF)a demonstrates a potent synergistic effect on interferon (IFN)g-induced CXCL10 secretion. We investigated the mechanism underlying the synergism between IFNg and TNFa and the effect of MMI on CXCL10 secretion in human thyrocytes. A peroxisome proliferatoractivated receptor g agonist, rosiglitazone (RGZ), a known inhibitor of T helper 1 (Th1)-mediated responses, was also studied for comparison. Experiments were carried out in human thyrocytes isolated from internodular parenchyma of thyroid tissues derived from patients who had undergone surgery for multinodular goiter. ELISA was used to measure CXCL10 levels in culture supernatant. Flow cytometry was used to assess IFNg membrane receptor expression. Specific mRNA analysis was performed by Taqman real-time PCR. Immunofluorescence was performed to detect nuclear translocation of nuclear factor-kB (NF-kB). In human thyrocytes, the synergistic effect of TNFa with IFNg on CXCL10 secretion is due to the upregulation of IFNg receptor expression. MMI decreased cytokine-induced CXCL10 secretion by reducing TNFa-induced upregulation of the IFNg receptor. RGZ decreased the cytokine-induced CXCL10 secretion by impairing NF-kB translocation, without affecting IFNg receptor. MMI and RGZ targeted thyrocytes with the same pharmacological potency, likely acting throughout different mechanisms. Targeting T helper 1-mediated autoimmune thyroid disease with drugs that impair different intracellular pathways could be a novel pharmacological tool.

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“…As shown in Table II ϩ , CD45 RO ϩ ), but they rather exhibit a central memory profile (CD62L ϩ CCR7 ϩ ). They also express CXCR3, a chemokine receptor that has been reported to enhance allergen-specific IFN-␥ production (34). (Fig.…”

Section: T Cells In Allergic and Nonallergic Individualsmentioning

confidence: 99%

Assessment of Bet v 1-Specific CD4+ T Cell Responses in Allergic and Nonallergic Individuals Using MHC Class II Peptide Tetramers

Overtvelt

Wambre

Maillère

et al. 2008

The Journal of Immunology

111

118

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In this study, we used HLA-DRB1*0101, DRB1*0401, and DRB1*1501 peptide tetramers combined with cytokine surface capture assays to characterize CD4+ T cell responses against the immunodominant T cell epitope (peptide 141–155) from the major birch pollen allergen Bet v 1, in both healthy and allergic individuals. We could detect Bet v 1-specific T cells in the PBMC of 20 birch pollen allergic patients, but also in 9 of 9 healthy individuals tested. Analysis at a single-cell level revealed that allergen-specific CD4+ T cells from healthy individuals secrete IFN-γ and IL-10 in response to the allergen, whereas cells from allergic patients are bona fide Th2 cells (producing mostly IL-5, some IL-10, but no IFN-γ), as corroborated by patterns of cytokines produced by T cell clones. A fraction of Bet v 1-specific cells isolated from healthy, but not allergic, individuals also expresses CTLA-4, glucocorticoid-induced TNF receptor, and Foxp 3, indicating that they represent regulatory T cells. In this model of seasonal exposure to allergen, we also demonstrate the tremendous dynamics of T cell responses in both allergic and nonallergic individuals during the peak pollen season, with an expansion of Bet v 1-specific precursors from 10−6 to 10−3 among circulating CD4+ T lymphocytes. Allergy vaccines should be designed to recapitulate such naturally protective Th1/regulatory T cell responses observed in healthy individuals.

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Allergic humans are hypo‐responsive to CXCR3 chemokines in a Th1 immunity‐promoting loop

Cited by 84 publications

References 53 publications

Effects of CXCL10 on Dendritic Cell and CD4⁺T-Cell Functions duringLeishmania amazonensisInfection

Effects of CXCL10 on Dendritic Cell and CD4⁺T-Cell Functions duringLeishmania amazonensisInfection

Methimazole inhibits CXC chemokine ligand 10 secretion in human thyrocytes

Assessment of Bet v 1-Specific CD4+ T Cell Responses in Allergic and Nonallergic Individuals Using MHC Class II Peptide Tetramers

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Allergic humans are hypo‐responsive to CXCR3 chemokines in a Th1 immunity‐promoting loop

Cited by 84 publications

References 53 publications

Effects of CXCL10 on Dendritic Cell and CD4+T-Cell Functions duringLeishmania amazonensisInfection

Effects of CXCL10 on Dendritic Cell and CD4+T-Cell Functions duringLeishmania amazonensisInfection

Methimazole inhibits CXC chemokine ligand 10 secretion in human thyrocytes

Assessment of Bet v 1-Specific CD4+ T Cell Responses in Allergic and Nonallergic Individuals Using MHC Class II Peptide Tetramers

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Product

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Effects of CXCL10 on Dendritic Cell and CD4⁺T-Cell Functions duringLeishmania amazonensisInfection

Effects of CXCL10 on Dendritic Cell and CD4⁺T-Cell Functions duringLeishmania amazonensisInfection