Transcriptional Regulation of Th2 Differentiation by Inducible Costimulator

Nurieva, Roza; Duong, Julie; Kishikawa, Hiroko; Dianzani, Umberto; Rojo, José María; Ho, I‐Cheng; Flavell, Richard A.; Dong, Chen

doi:10.1016/s1074-7613(03)00144-4

Cited by 133 publications

(127 citation statements)

References 57 publications

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“…(B6 ϫ bm12)F 1 and (B6 ϫ bm3)F 1 mice were bred in our animal facility. ICOSdeficient mice on B6 or DBA1 background were previously described (4,22). The B7h knockout strain was previously generated as described elsewhere (23).…”

Section: Micementioning

confidence: 99%

Opposing Effects of ICOS on Graft-versus-Host Disease Mediated by CD4 and CD8 T Cells

Liang

Nurieva

et al. 2006

The Journal of Immunology

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ICOS, a CD28 family member expressed on activated CD4+ and CD8+ T cells, plays important roles in T cell activation and effector function. Here we studied the role of ICOS in graft-vs-host disease (GVHD) mediated by CD4+ or CD8+ T cells in allogeneic bone marrow transplantation. In comparison of wild-type and ICOS-deficient T cells, we found that recipients of ICOS−/− CD4+ T cells exhibited significantly less GVHD morbidity and delayed mortality. ICOS−/− CD4+ T cells had no defect in expansion, but expressed significantly less Fas ligand and produced significantly lower levels of IFN-γ and TNF-α. Thus, ICOS−/− CD4+ T cells were impaired in effector functions that lead to GVHD. In contrast, recipients of ICOS−/− CD8+ T cells exhibited significantly enhanced GVHD morbidity and accelerated mortality. In the absence of ICOS signaling, either using ICOS-deficient donors or ICOS ligand-deficient recipients, the levels of expansion and Tc1 cytokine production of CD8+ T cells were significantly increased. The level of expansion was inversely correlated with the level of apoptosis, suggesting that increased ability of ICOS−/− CD8+ T cells to induce GVHD resulted from the enhanced survival and expansion of those cells. Our findings indicate that ICOS has paradoxical effects on the regulation of alloreactive CD4+ and CD8+ T cells in GVHD.

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Section: Micementioning

confidence: 99%

Opposing Effects of ICOS on Graft-versus-Host Disease Mediated by CD4 and CD8 T Cells

Liang

Nurieva

et al. 2006

The Journal of Immunology

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“…The few data from humans point to a different behavior. For instance, our work in the mouse suggests that IL-4 and ICOS build up a positive feedback loop, in which initial secretion of small amounts of IL-4 induces expression of ICOS, whose triggering then enhances IL-4 secretion [31,32], whereas in humans ICOS expression appears to be up-regulated by IL-12 and IL-23, and is higher in Th1 than in Th2 cells, and ICOS itself appears to play no part in Th1:Th2 polarization [33,34].…”

Section: Introductionmentioning

confidence: 99%

ICOS cooperates with CD28, IL‐2, and IFN‐γ and modulates activation of human naïve CD4⁺ T cells

et al. 2006

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Several sets of data indicate that ICOS regulates cytokine production in activated T cells, but is less effective on naïve T cells. This work evaluates ICOS function in human naïve CD4 + T cells through an assessment of the effect of soluble forms of the ICOS and CD28 physiological ligands on activation driven by anti-CD3 mAb. ICOS strikingly potentiated secretion of IL-2, IFN-c, IL-10, and TNF-a, but not IL-4, promoted by optimal stimulation of CD3+CD28, and it was the key switching-factor of activation when cells received suboptimal stimulation of CD3+CD28 or stimulation of CD3 alone in the presence of exogenous IL-2. In these conditions, blockade of IL-2 and IFN-c showed that ICOS builds up a positive feedback loop with IFN-c, which required IL-2 and was inhibited by IL-4. By contrast, in the absence of CD28 triggering or exogenous IL-2, ICOS-induced costimulation mainly supported expression of TGF-b1 and FoxP3 and differentiation of regulatory T cells capable to inhibit proliferation of naïve CD4 + T cells driven by allogeneic cells. These data suggest that ICOS favors differentiation of Th effector cells when cooperates with appropriate activation stimuli such as CD3+CD28 or CD3+IL-2, whereas it supports differentiation of regulatory T cells when costimulatory signals are insufficient.

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“…Notably, ICOS is a CD28 superfamily-related molecule, which plays an important role in T cell activation/survival (18). ICOS enhances IL-4 and IL-10 secretion in Th2 cell responses (18,19), and blockade of the ICOS-ICOS-ligand pathway during the induction of Th1-driven experimental autoimmune encephalomyelitis exacerbated disease by enhancing IFN-g production (20). Notably, ICOS mRNA is abundantly expressed in pancreatic lymph nodes (pLNs) of T1D-protected BDC2.5-NOD (BDC2.5) TCR transgenic mice (21).…”

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ICOS-Dependent Homeostasis and Function of Foxp3+ Regulatory T Cells in Islets of Nonobese Diabetic Mice

Kornete

Sgouroudis

Piccirillo

2012

The Journal of Immunology

129

145

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A progressive waning in Foxp3+ regulatory T cell (Treg) functions is thought to provoke autoimmunity in the NOD model of type 1 diabetes (T1D). A deficiency in IL-2 is one of the main triggers for the defective function of Tregs in islets. Notably, abrogation of the ICOS pathway in NOD neonates or BDC2.5-NOD (BDC2.5) mice exacerbates T1D, suggesting an important role for this costimulatory pathway in tolerance to islet Ags. Thus, we hypothesize that ICOS selectively promotes Foxp3+ Treg functions in BDC2.5 mice. We show that ICOS expression discriminates effector Foxp3− T cells from Foxp3+ Tregs and specifically designates a dominant subset of intra-islet Tregs, endowed with an increased potential to expand, secrete IL-10, and mediate suppressive activity in vitro and in vivo. Consistently, Ab-mediated blockade or genetic deficiency of ICOS selectively abrogates Treg-mediated functions and T1D protection and exacerbates disease in BDC2.5 mice. Moreover, T1D progression in BDC2.5 mice is associated with a decline in ICOS expression in and expansion and suppression by intra-islet Foxp3+ Tregs. We further show that the ICOS+ Tregs, in contrast to their ICOS− counterparts, are more sensitive to IL-2, a critical signal for their survival and functional stability. Lastly, the temporal loss in ICOS+ Tregs is readily corrected by IL-2 therapy or protective Il2 gene variation. Overall, ICOS is critical for the homeostasis and functional stability of Foxp3+ Tregs in prediabetic islets and maintenance of T1D protection.

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Transcriptional Regulation of Th2 Differentiation by Inducible Costimulator

Cited by 133 publications

References 57 publications

Opposing Effects of ICOS on Graft-versus-Host Disease Mediated by CD4 and CD8 T Cells

Opposing Effects of ICOS on Graft-versus-Host Disease Mediated by CD4 and CD8 T Cells

ICOS cooperates with CD28, IL‐2, and IFN‐γ and modulates activation of human naïve CD4⁺ T cells

ICOS-Dependent Homeostasis and Function of Foxp3+ Regulatory T Cells in Islets of Nonobese Diabetic Mice

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Transcriptional Regulation of Th2 Differentiation by Inducible Costimulator

Cited by 133 publications

References 57 publications

Opposing Effects of ICOS on Graft-versus-Host Disease Mediated by CD4 and CD8 T Cells

Opposing Effects of ICOS on Graft-versus-Host Disease Mediated by CD4 and CD8 T Cells

ICOS cooperates with CD28, IL‐2, and IFN‐γ and modulates activation of human naïve CD4+ T cells

ICOS-Dependent Homeostasis and Function of Foxp3+ Regulatory T Cells in Islets of Nonobese Diabetic Mice

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ICOS cooperates with CD28, IL‐2, and IFN‐γ and modulates activation of human naïve CD4⁺ T cells