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PI3K p110δ regulates T-cell cytokine production during primary and secondary immune responses in mice and humans

2010; Elsevier BV; Volume: 115; Issue: 11 Linguagem: Inglês

10.1182/blood-2009-07-232330

1528-0020

Dalya R. Soond, Elisa Bjørgo, Kristine Moltu, Verity Q. Dale, Daniel T. Patton, Knut Martin Torgersen, Fiona P. Galleway, Breda M. Twomey, Jonathan Clark, J. S. Hill Gaston, Kjetil Taskén, Peter Bunyard, Klaus Okkenhaug,

Cytokine Signaling Pathways and Interactions

Abstract We have previously described critical and nonredundant roles for the phosphoinositide 3-kinase p110δ during the activation and differentiation of naive T cells, and p110δ inhibitors are currently being developed for clinical use. However, to effectively treat established inflammatory or autoimmune diseases, it is important to be able to inhibit previously activated or memory T cells. In this study, using the isoform-selective inhibitor IC87114, we show that sustained p110δ activity is required for interferon-γ production. Moreover, acute inhibition of p110δ inhibits cytokine production and reduces hypersensitivity responses in mice. Whether p110δ played a similar role in human T cells was unknown. Here we show that IC87114 potently blocked T-cell receptor–induced phosphoinositide 3-kinase signaling by both naive and effector/memory human T cells. Importantly, IC87114 reduced cytokine production by memory T cells from healthy and allergic donors and from inflammatory arthritis patients. These studies establish that previously activated memory T cells are at least as sensitive to p110δ inhibition as naive T cells and show that mouse models accurately predict p110δ function in human T cells. There is therefore a strong rationale for p110δ inhibitors to be considered for therapeutic use in T-cell–mediated autoimmune and inflammatory diseases.