Effector Functions of Donor-Reactive CD8 Memory T Cells Are Dependent on ICOS Induced During Division in Cardiac Grafts

Authors

  • A. D. Schenk,

    Corresponding author
    1. Department of Pathology, Case Western Reserve University, Cleveland, OH
    2. Glickman Urological Institute and Department of Immunology, Cleveland Clinic Foundation, Cleveland, OH
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  • V. Gorbacheva,

    1. Glickman Urological Institute and Department of Immunology, Cleveland Clinic Foundation, Cleveland, OH
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  • M. Rabant,

    1. Glickman Urological Institute and Department of Immunology, Cleveland Clinic Foundation, Cleveland, OH
    2. Service de Transplantation Rénale, Hôpital Necker, Paris Cedex, France
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  • R. L. Fairchild,

    1. Department of Pathology, Case Western Reserve University, Cleveland, OH
    2. Glickman Urological Institute and Department of Immunology, Cleveland Clinic Foundation, Cleveland, OH
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  • A. Valujskikh

    1. Glickman Urological Institute and Department of Immunology, Cleveland Clinic Foundation, Cleveland, OH
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Abstract

Alloreactive T-cell memory is present in every transplant recipient and endangers graft survival. Even in the absence of known sensitizing exposures, heterologous immunity and homeostatic T-cell proliferation generate ‘endogenous' memory T cells with donor-reactivity. We have recently shown that endogenous donor-reactive CD8 memory T cells infiltrate murine cardiac allografts within hours of reperfusion and amplify early posttransplant inflammation by producing IFN-γ. Here, we have tested the role of ICOS co-stimulation in eliciting effector function from these memory T cells. ICOS is not expressed on the cell surface of circulating CD8 memory T cells but is rapidly upregulated during cell division within the allograft parenchyma. Donor-reactive CD8 memory T-cell infiltration, proliferation and ICOS expression are regulated by donor class I MHC molecule expression. ICOS blockade significantly reduced IFN-γ production and other proinflammatory functions of the activated CD8 memory T cells. Our data demonstrate that this induction of ICOS expression within peripheral tissues is an important feature of CD8 memory T-cell activation and identify ICOS as a specific target for neutralizing proinflammatory functions of endogenous CD8 memory T cells.

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