Regulation of Mouse Inducible Costimulator (ICOS) Expression by Fyn-NFATc2 and ERK Signaling in T Cells

Tan, Andy Hee-Meng; Wong, Sek-Man; Lam, Kong-Peng

doi:10.1074/jbc.m604081200

Cited by 41 publications

(50 citation statements)

References 49 publications

(48 reference statements)

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“…In contrast to naive T cells, ICOS is constitutively expressed on memory phenotype CD4 ϩ T cells (25) and is also expressed on some subsets of CD25 ϩ CD4 ϩ regulatory T cells (26). Promoter analysis suggests that NFAT and AP-1 may be involved in ICOS gene transcription (27). In contrast, it has been reported that ICOS gene expression is negatively regulated by Roquin (22).…”

mentioning

confidence: 78%

Down-Regulation of ICOS Ligand by Interaction with ICOS Functions as a Regulatory Mechanism for Immune Responses

Watanabe

Takagi

Kotani³

et al. 2008

The Journal of Immunology

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Although it is well-known that the ICOS-ICOS ligand (ICOSL) costimulatory pathway is important for many immune responses, recent accumulated evidence suggests that dysregulation of this pathway may lead to and/or exaggerate autoimmune responses. ICOS is induced on the cell surface after T cell activation. Similarly, ICOSL is up-regulated on APCs by several mitogenic stimuli. However, the mechanism regulating expression of the ICOS-ICOSL pair, and the significance of controlling their expression for an appropriate immune response, is largely unknown. To gain a better understanding of the importance of fine control of the ICOS-ICOSL costimulatory pathway, we generated ICOS-transgenic (Tg) mice that have high constitutive expression of ICOS in all T cells. Using ICOS-Tg mice, we studied whether in vivo immune responses were affected. Unexpectedly, we first found that ICOS-Tg mice exhibited a phenotype resembling ICOS-deficient mice in their Ag-specific Ab response, such as a defect in class switch recombination. Further examination revealed that ICOSL expression of APCs was significantly suppressed in ICOS-Tg mice. Interestingly, suppression of ICOSL was induced by interaction of ICOSL with ICOS, and it seemed to be regulated at the posttranscriptional level. The suppressive effect of the ICOS-ICOSL interaction overcame the positive effect of CD40 or B cell activation factor of the TNF family (BAFF) stimulation on ICOSL expression. Together, our studies demonstrate a novel mechanism for the regulation of ICOSL expression in vivo and suggest that the ICOS costimulatory pathway is subject to negative feedback regulation by ICOSL down-regulation in response to ICOS expression.

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confidence: 78%

Down-Regulation of ICOS Ligand by Interaction with ICOS Functions as a Regulatory Mechanism for Immune Responses

Watanabe

Takagi

Kotani³

et al. 2008

The Journal of Immunology

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“…Using mice eradicated of commensal bacteria, we also made the curious observation that re-establishing intestinal colonization with C. albicans alone does not induce ICOS expression by lamina propria CD4 + T cells. Whether this reflects discordant cell activation induced by C. ablicans compared with commensal enteric bacteria through TLR4 or NFAT that each promote CD4 + T-cell ICOS expression is uncertain, but represents an important area for future investigation (40,41).…”

Section: Discussionmentioning

confidence: 99%

Commensal microbes drive intestinal inflammation by IL-17–producing CD4 ⁺ T cells through ICOSL and OX40L costimulation in the absence of B7-1 and B7-2

Luo¹,

Jiang²,

Chaturvedi³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The costimulatory B7-1 (CD80)/B7-2 (CD86) molecules, along with T-cell receptor stimulation, together facilitate T-cell activation. This explains why in vivo B7 costimulation neutralization efficiently silences a variety of human autoimmune disorders. Paradoxically, however, B7 blockade also potently moderates accumulation of immune-suppressive regulatory T cells (Tregs) essential for protection against multiorgan systemic autoimmunity. Here we show that B7 deprivation in mice overrides the necessity for Tregs in averting systemic autoimmunity and inflammation in extraintestinal tissues, whereas peripherally induced Tregs retained in the absence of B7 selectively mitigate intestinal inflammation caused by Th17 effector CD4 + T cells. The need for additional immune suppression in the intestine reflects commensal microbe-driven T-cell activation through the accessory costimulation molecules ICOSL and OX40L. Eradication of commensal enteric bacteria mitigates intestinal inflammation and IL-17 production triggered by Treg depletion in B7-deficient mice, whereas re-establishing intestinal colonization with Candida albicans primes expansion of Th17 cells with commensal specificity. Thus, neutralizing B7 costimulation uncovers an essential role for Tregs in selectively averting intestinal inflammation by Th17 CD4 + T cells with commensal microbe specificity.

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“…EL4 cells were plated, transfected with empty or caMEK2 expressing vector, stimulated with PMA and ionomycin, and harvested 16 h later for RNA extraction as described (34). Real-time RT-PCR analyses of il-17a, il17f, and il-22 transcripts were then performed as described above.…”

Section: Transfection Of El4 Cellsmentioning

confidence: 99%

Pharmacologic Inhibition of MEK–ERK Signaling Enhances Th17 Differentiation

Tan

Lam

2010

The Journal of Immunology

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The cytokines and transcription factors that promote Th17 cell development have been extensively studied. However, the signaling pathways that antagonize Th17 differentiation remain poorly characterized. In this study, we report that pharmacologic inhibition of MEK–ERK signaling enhances the in vitro differentiation of Th17 cells and increases their gene expression of il-17a, il-17f, il-21, il-22, and il-23r. IL-2, which suppresses Th17 differentiation via STAT5 activation, also acts through ERK signaling to inhibit Th17 generation. In turn, ERK signaling is found to potentiate the production of IL-2 and activate STAT5, suggesting the existence of an autoregulatory loop to constrain Th17 development. Finally, compared with the transfer of untreated Th17 cells, the transfer of ERK-inhibited Th17 cells leads to accelerated onset and exacerbated colitis in immunodeficient mice. Our data indicate that MEK–ERK signaling negatively regulates Th17 differentiation in a Th cell-intrinsic manner.

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Regulation of Mouse Inducible Costimulator (ICOS) Expression by Fyn-NFATc2 and ERK Signaling in T Cells

Cited by 41 publications

References 49 publications

Down-Regulation of ICOS Ligand by Interaction with ICOS Functions as a Regulatory Mechanism for Immune Responses

Down-Regulation of ICOS Ligand by Interaction with ICOS Functions as a Regulatory Mechanism for Immune Responses

Commensal microbes drive intestinal inflammation by IL-17–producing CD4 ⁺ T cells through ICOSL and OX40L costimulation in the absence of B7-1 and B7-2

Pharmacologic Inhibition of MEK–ERK Signaling Enhances Th17 Differentiation

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Regulation of Mouse Inducible Costimulator (ICOS) Expression by Fyn-NFATc2 and ERK Signaling in T Cells

Cited by 41 publications

References 49 publications

Down-Regulation of ICOS Ligand by Interaction with ICOS Functions as a Regulatory Mechanism for Immune Responses

Down-Regulation of ICOS Ligand by Interaction with ICOS Functions as a Regulatory Mechanism for Immune Responses

Commensal microbes drive intestinal inflammation by IL-17–producing CD4 + T cells through ICOSL and OX40L costimulation in the absence of B7-1 and B7-2

Pharmacologic Inhibition of MEK–ERK Signaling Enhances Th17 Differentiation

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Commensal microbes drive intestinal inflammation by IL-17–producing CD4 ⁺ T cells through ICOSL and OX40L costimulation in the absence of B7-1 and B7-2