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

Yu, Xue-Zhong; Liang, Yu; Nurieva, Roza; Guo, Fei; Anasetti, Claudio; Dong, Chen

doi:10.4049/jimmunol.176.12.7394

Cited by 42 publications

(24 citation statements)

References 44 publications

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“…The latter concept is supported by our data obtained in in-vitro apoptosis assays revealing that T cell stimulation in the presence of ICOS agonist predisposes CD8 + (but not CD4 + ) T cells for death by apoptosis ( Figure 2 ). This is well in line with another study that demonstrated differential effects of ICOS on CD4 + and CD8 + T cells with an increased ability of ICOS −/− CD8 + T cells to induce Graft-versus-Host Disease (GvHD) as a result of enhanced survival and expansion of those cells [40].…”

Section: Discussionsupporting

confidence: 89%

Attenuation of Immune-Mediated Influenza Pneumonia by Targeting the Inducible Co-Stimulator (ICOS) Molecule on T Cells

et al. 2014

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Inducible Co-stimulator (ICOS) plays a critical role in mediating T cell differentiation and function and is considered a key player in balancing T effector and T regulatory (Treg) cell responses. Here we show that activation of the ICOS signalling pathway during acute influenza A virus (IAV) infection by application of an agonistic ICOS antibody reduced the frequency of CD8+ T cells in the respiratory tract of IAV infected animals and delayed pathogen elimination. In line with this, immune-mediated influenza pneumonia was significantly ameliorated in mice that received ICOS agonist as indicated by significantly reduced alveolar infiltrations and bronchointerstitial pneumonia, while at the same time virus-related pathology remained unaffected. Importantly, ICOS agonist treatment resulted in expansion of CD4+Foxp3+ Tregs in IAV infected mice, which was associated with elevated levels of the immunosuppressive cytokine IL-10 in the alveolar space. Together, our findings suggest a prominent role of ICOS signaling during acute IAV infection by increasing the Treg/CD8+ T cell ratio with beneficial outcome on immune-mediated pneumonia and underline the suitability of ICOS as potential therapeutic target for immune intervention in those infectious conditions characterized by strong immunopathology rather than virus-mediated cytopathic effects.

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Section: Discussionsupporting

confidence: 89%

Attenuation of Immune-Mediated Influenza Pneumonia by Targeting the Inducible Co-Stimulator (ICOS) Molecule on T Cells

et al. 2014

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“…Given that un-programmed CD8 + T cells deficient in ICOS expand to a greater extent than WT counterparts in a GVHD model (29), we hypothesized that Tc17 (but not Th17) cells deficient in ICOS would expand to a greater extent than WT Tc17 cells. Indeed, ICOS −/− Tc17 cells expanded to a slightly greater extent than WT Tc17 cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

The Inducible Costimulator Augments Tc17 Cell Responses to Self and Tumor Tissue

Nelson

Kundimi

Bowers

et al. 2015

The Journal of Immunology

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The inducible costimulator (ICOS) plays a key role in CD4+ Th17 cell development, but its role in CD8+ Tc17 cell development and self/tumor immunity remains unknown. We found that ICOS co-stimulation was important for the functional maintenance but not differentiation of Tc17 cells in vitro. Blocking the ICOS pathway using an antagonist antibody or by using mice genetically deficient in the ICOS ligand (ICOSL) reduced the antitumor activity of adoptively transferred Tc17 cells. Conversely, activating Tc17 cells with an ICOS agonist in vitro enhanced their capacity to eradicate melanoma and induce autoimmune vitiligo when infused into mice. However, ICOS stimulation did not augment the antitumor activity of IL-2 expanded T cells. Additional investigation revealed that ICOS stimulation not only increased IL-2Rα, CXCR3 and IL-23R expression on Tc17 cells, but also dampened their expression of suppressive molecule CD39. Although Tc17 cells activated with an ICOS agonist co-secreted heightened IL-17A, IL-9 and IFN-γ, their therapeutic effectiveness was critically dependent on IFN-γ production. Depletion of IL-17A and IL-9 had little impact of antitumor Tc17 cells activated with an ICOS agonist. Collectively, our work reveals that the ICOS pathway potentiates the antitumor activity of adoptively transferred Tc17 cells. This work has major implications for the design of vaccine, antibody and cell-based therapies for autoimmunity, infectious disease and cancer.

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“…This proliferative effect of ICOS costimulation is not appreciable during in vivo immune responses presumably due to a dominant effect of CD28 (3). However, ICOS does play critical roles in generation of follicular Th cells (4), antitumor T cell responses (5), and graft-versus-host disease (GVHD) (6–9). These impacts are related to augmented expression of an array of Th1 and Th2 cytokines, including IFN-γ, IL-4, IL-10, and IL-21 by ICOS costimulation.…”

mentioning

confidence: 99%

“…Results from another group indicated that ICOS blockade reduced GVHD while largely sparing graft-versus-leukemia activity by skewing toward Th2 differentiation, without affecting T cell activation, proliferation, cytotoxicity, and target organ infiltration (6). Studies by our own group indicate that ICOS deficiency or blockade results in significantly less GVHD morbidity and delayed mortality (7, 9). The effect of ICOS is predominately on CD4 T cells, and the deficiency of ICOS had no impact on their expansion, but significantly reduced their effector functions in term of expression in FasL and production of IFN-γ and TNF-α (9).…”

mentioning

confidence: 99%

Phosphatidylinositol 3-Kinase–Independent Signaling Pathways Contribute to ICOS-Mediated T Cell Costimulation in Acute Graft-Versus-Host Disease in Mice

Heinrichs

Leconte

et al. 2013

The Journal of Immunology

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We and others have previously shown that ICOS plays an important role in inducing acute graft-versus-host disease (GVHD) in murine models of allogeneic bone marrow transplantation. ICOS potentiates TCR-mediated PI3K activation and intracellular calcium mobilization. However, ICOS signal transduction pathways involved in GVHD remain unknown. In this study, we examined the contribution of ICOS-PI3K signaling in the pathogenic potential of T cells using a knock-in mouse strain, ICOS-YF, which selectively lost the ability to activate PI3K. We found that when total T cells were used as alloreactive T cells, ICOS-YF T cells caused less severe GVHD compared with ICOS wild-type T cells, but they induced much more aggressive disease than ICOS knockout T cells. This intermediate level of pathogenic capacity of ICOS-YF T cells was correlated with similar levels of IFN-g–producing CD8 T cells that developed in the recipients of ICOS-WT or ICOS-YF T cells. We further evaluated the role of ICOS-PI3K signaling in CD4 versus CD8 T cell compartment using GVHD models that are exclusively driven by CD4 or CD8 T cells. Remarkably, ICOS-YF CD8 T cells caused disease similar to ICOS wild-type CD8 T cells, whereas ICOS-YF CD4 T cells behaved very similarly to their ICOS knockout counterparts. Consistent with their in vivo pathogenic potential, CD8 T cells responded to ICOS ligation in vitro by PI3K-independent calcium flux, T cell activation, and proliferation. Thus, in acute GVHD in mice, CD4 T cells heavily rely on ICOS-PI3K signaling pathways; in contrast, CD8 T cells can use PI3K-independent ICOS signaling pathways, possibly through calcium.

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

Cited by 42 publications

References 44 publications

Attenuation of Immune-Mediated Influenza Pneumonia by Targeting the Inducible Co-Stimulator (ICOS) Molecule on T Cells

Attenuation of Immune-Mediated Influenza Pneumonia by Targeting the Inducible Co-Stimulator (ICOS) Molecule on T Cells

The Inducible Costimulator Augments Tc17 Cell Responses to Self and Tumor Tissue

Phosphatidylinositol 3-Kinase–Independent Signaling Pathways Contribute to ICOS-Mediated T Cell Costimulation in Acute Graft-Versus-Host Disease in Mice

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