Differential expression of the cytokine receptors for human interleukin (IL)-12 and IL-18 on lymphocytes of both CD45RA+ and CD45RO+ phenotype from tonsils, cord and adult peripheral blood

Bofill, Margarita; Almirall, E.; McQuaid, A; Peña, Ruth; Ruiz-Hernández, Raul; Naranjo, M.; Ruiz, Lı́dia; Clotet, Bonaventura; Borràs, Francesc E.

doi:10.1111/j.1365-2249.2004.02651.x

Cited by 13 publications

(13 citation statements)

References 20 publications

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“…In accordance with earlier studies, 19 we were not able to detect IL-12R␤2 expression on resting memory Th cells by flow cytometry (data not shown). To detect low but functional IL-12 receptor expression in IL-18R␣ ϩ and IL-18R␣ Ϫ memory Th cells purified from peripheral blood, we assessed IL-12R-dependent STAT4 phosphorylation (pSTAT4) by immunoblotting.…”

Section: Cytokine-induced Ifn-␥ Secretion Is Confined To Ccr7 ؊ Ccr5 supporting

confidence: 76%

“…26,33 So far, functional IL-12R expression among Th cells was exclusively attributed to recently activated Th1 cells. 19 We demonstrate, however, that functional receptors for IL-12 are also expressed by resting peripheral IL-18R␣ ϩ Th cells reflected by STAT4 phosphorylation on IL-12 stimulation. Whether the observed receptor expression pattern is stable over time in vivo after initial Th1 polarization or results from recurrent antigenic reactivation is currently under investigation.…”

Section: Discussionmentioning

confidence: 98%

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Cytokine-induced human IFN-γ–secreting effector-memory Th cells in chronic autoimmune inflammation

Sattler

Wagner

Rossol

et al. 2009

Blood

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IntroductionProduction of interferon-␥ (IFN-␥) by T-helper1 (Th1) cells is a key feature of both protective and pathologic immune responses. Control and clearance of bacterial and viral infections strictly depend on antigen-specific IFN-␥-secreting Th cells. 1,2 It is also undisputed that Th1 cells of the effector-memory phenotype predominate in inflamed tissues in human autoimmune diseases, such as rheumatoid arthritis (RA), [3][4][5] where they compose up to 80% of the T-cell infiltrate. 6 Nonetheless, how such cells get activated at sites of chronic inflammation remains an unsolved issue. Recent reports have challenged the concept that IFN-␥ release by T cells strictly depends on T-cell receptor (TCR) ligation: in in vitro-generated murine Th1-effector cells, IFN-␥ production is inducible in a TCR-independent manner by the cytokines interleukin-12 (IL-12) and IL-18. 7 IL-12R-downstream STAT4 and IL-18R-dependent GADD45-␤, which activates p38 mitogen-activated protein kinase (MAPK), were identified as essential signaling components. 8,9 Although infection models suggest that such a mechanism evolved to provide an early source of IFN-␥ contributing to host protection, 10,11 it was at the same time postulated to promote inflammatory circuits in autoimmunity. 12 In contrast to murine Th1 cells, however, stimulation of human resting Th cells with IL-12 and IL-18 induces only minute amounts of IFN-␥ 13 but boosts cytokine production in synergy with TCR ligation. 14 Th cells isolated from synovial infiltrates of RA patients exhibit a differentiated effector-memory Th1 phenotype, reflected, for example, by expression of IL-12R and IL-18R. 15 Because elevated levels of several proinflammatory mediators, including IL-12 and IL-18, were found to correlate with disease severity, 16,17 we wondered whether cytokine-induced IFN-␥ production in human Th cells in the absence of antigenic stimulation is functional at all in vitro and of relevance in vivo in human autoimmunity.We demonstrate here that a subset of human resting effectormemory Th cells, characterized by ex vivo expression of IL-18R␣, IL-12R, and CCR5, can be induced to secrete IFN-␥ by cytokines present at sites of chronic inflammation. IL-2R ␥-chain (␥ c ) signaling via JAK3, in addition to IL-12R and IL-18R ligation, is essential for TCR-independent induction of IFN-␥ production. Cytokine-induced IFN-␥ ϩ Th cells are sensitive to suppression by CD25 ϩϩ T regulatory cells and specifically lack 4-1BB (CD137) expression. Applying this activation marker, we provide evidence that almost all Th cells spontaneously secreting IFN-␥ ex vivo in synovial infiltrates from RA patients are cytokine-induced, for they characteristically lack 4-1BB expression. Our results support the notion that IFN-␥ production by Th cells in chronic autoimmune inflammation may be provoked solely by the cytokine environment, independent of triggering autoantigens. Methods Cell isolationPeripheral blood mononuclear cells (PBMCs) were isolated from peripheral blood of healthy donors by Ficoll-Hy...

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Section: Cytokine-induced Ifn-␥ Secretion Is Confined To Ccr7 ؊ Ccr5 supporting

confidence: 76%

Section: Discussionmentioning

confidence: 98%

Cytokine-induced human IFN-γ–secreting effector-memory Th cells in chronic autoimmune inflammation

Sattler

Wagner

Rossol

et al. 2009

Blood

View full text Add to dashboard Cite

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“…IL18R1 (52), NOD2 (53), FLT1 (54), CCL3, CCL5 (55), ITGB7 (56)), many have not been linked specifically to either subset in the literature (AIM2, EMP1, ANK3, MPEG1; Table II). To obtain a more complete understanding of which functions might be regulated by CpG methylation as revealed in our data, functional pathway mapping was conducted.…”

Section: Discussionmentioning

confidence: 99%

Defining CD4 T Cell Memory by the Epigenetic Landscape of CpG DNA Methylation

Komori

Hart

LaMere

et al. 2015

The Journal of Immunology

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Memory T cells are primed for rapid responses to antigen; however, the molecular mechanisms responsible for priming remain incompletely defined. CpG methylation in promoters is an epigenetic modification, which regulates gene transcription. Using targeted bisulfite sequencing, we examined methylation of 2100 genes (56,000 CpG) mapped by deep sequencing of T cell activation in human naïve and memory CD4 T cells. 466 CpGs (132 genes) displayed differential methylation between naïve and memory cells. 21 genes exhibited both differential methylation and gene expression before activation, linking promoter DNA methylation states to gene regulation; 6 of 21 genes encode proteins closely studied in T cells, while 15 genes represent novel targets for further study. 84 genes demonstrated differential methylation between memory and naïve cells that correlated to differential gene expression following activation, of which 39 exhibited reduced methylation in memory cells coupled with increased gene expression upon activation compared to naïve cells. These reveal a class of primed genes more rapidly expressed in memory compared to naïve cells and putatively regulated by DNA methylation. These findings define a DNA methylation signature unique to memory CD4 T cells that correlates with activation-induced gene expression.

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“…IL‐12 receptor beta 1 (Rβ1) is essential for the enhancement of IL‐12‐mediated alloantigen‐specific immune response 22. It has been reported that IL‐12 receptors are expressed more highly in memory rather than in naive T cell subsets after the activation of T cells 23. Here, we investigated how preoperative levels of IL‐12Rβ1 + cells influence the phenotype and function of CD8 + T cell subpopulations after LDLT, associated with changes of IFN‐γ, tumor necrosis factor‐alpha, and perforin expression.…”

mentioning

confidence: 98%

Laryngeal inflammatory myofibroblastic tumors: Different clinical appearance and histomorphologic presentation of one entity

et al. 2009

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Differential expression of the cytokine receptors for human interleukin (IL)-12 and IL-18 on lymphocytes of both CD45RA+ and CD45RO+ phenotype from tonsils, cord and adult peripheral blood

Cited by 13 publications

References 20 publications

Cytokine-induced human IFN-γ–secreting effector-memory Th cells in chronic autoimmune inflammation

Cytokine-induced human IFN-γ–secreting effector-memory Th cells in chronic autoimmune inflammation

Defining CD4 T Cell Memory by the Epigenetic Landscape of CpG DNA Methylation

Laryngeal inflammatory myofibroblastic tumors: Different clinical appearance and histomorphologic presentation of one entity

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