Article

PI3K p110 regulates T-cell cytokine production during primary and secondary immune responses in mice and humans

Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge, United Kingdom.
Blood (Impact Factor: 10.45). 03/2010; 115(11):2203-13. DOI: 10.1182/blood-2009-07-232330
Source: PubMed

ABSTRACT

We have previously described critical and nonredundant roles for the phosphoinositide 3-kinase p110delta during the activation and differentiation of naive T cells, and p110delta 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 p110delta activity is required for interferon-gamma production. Moreover, acute inhibition of p110delta inhibits cytokine production and reduces hypersensitivity responses in mice. Whether p110delta 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 p110delta inhibition as naive T cells and show that mouse models accurately predict p110delta function in human T cells. There is therefore a strong rationale for p110delta inhibitors to be considered for therapeutic use in T-cell-mediated autoimmune and inflammatory diseases.

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Available from: Dalya R Rosner, Nov 10, 2015
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    • "It has been shown that p110d is important for development, differentiation, and regulation of T cell subsets (Patton et al., 2007; Okkenhaug, 2013). Emerging evidence suggests that p110d is an attractive pharmacological target to modulate both unwanted immune responses and certain blood cancers (Soond et al., 2010; Billottet et al., 2006; Sujobert et al., 2005). Indeed, p110d-selective inhibitors are currently being tested in clinical trials to treat autoimmunity , allergy, and lymphoid malignancies. "
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    ABSTRACT: This is the final published version. It originally appeared in Cell Reports,10, 702–710 February 10, 2015, DOI: 10.1016/j.celrep.2015.01.002.
    Full-text · Article · Apr 2015
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    • "It has been shown that p110d is important for development, differentiation, and regulation of T cell subsets (Patton et al., 2007; Okkenhaug, 2013). Emerging evidence suggests that p110d is an attractive pharmacological target to modulate both unwanted immune responses and certain blood cancers (Soond et al., 2010; Billottet et al., 2006; Sujobert et al., 2005). Indeed, p110d-selective inhibitors are currently being tested in clinical trials to treat autoimmunity , allergy, and lymphoid malignancies. "
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    ABSTRACT: Allogeneic hematopoietic stem cell transplantation (HSCT) can treat certain hematologic malignancies due to the graft versus leukemia (GvL) effect but is complicated by graft versus host disease (GvHD). Expression of the p110δ catalytic subunit of the phosphoinositide 3-kinase pathway is restricted to leukocytes, where it regulates proliferation, migration, and cytokine production. Here, in a mouse model of fully mismatched hematopoietic cell transplantation (HCT), we show that genetic inactivation of p110δ in T cells leads to milder GvHD, whereas GvL is preserved. Inactivation of p110δ in human lymphocytes reduced T cell allorecognition. We demonstrate that both allostimulation and granzyme B expression were dependent on p110δ in naive T cells, which are the main mediators of GvHD, whereas memory T cells were unaffected. Strikingly, p110δ is not mandatory for either naive or memory T cells to mediate GvL. Therefore, immunomodulation of selective naive T cell functions by p110δ inactivation improves the outcome of allogeneic HSCT. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Feb 2015 · Cell Reports
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    • "To inhibit p110δ we used IC87114, a highly selective compound (Table 1) that has been widely used in lymphocyte studies [39], [40] and impairs NK cell chemotaxis at 1 µM [28]. At concentrations higher than 1 µM, IC87114 has off-target effects [40]. To inhibit p110γ we used the compound AS252424 (Table 1) at a concentration (1 µM) used in previous studies of NK cells [24], [28]. "
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    ABSTRACT: Phosphoinositide 3-kinases (PI3Ks) are promising targets for therapeutic development in cancer. The class I PI3K isoform p110α has received considerable attention in oncology because the gene encoding p110α (PIK3CA) is frequently mutated in human cancer. However, little is known about the function of p110α in lymphocyte populations that modulate tumorigenesis. We used recently developed investigational inhibitors to compare the function of p110α and other isoforms in natural killer (NK) cells, a key cell type for immunosurveillance and tumor immunotherapy. Inhibitors of all class I isoforms (pan-PI3K) significantly impaired NK cell-mediated cytotoxicity and antibody-dependent cellular cytotoxicity against tumor cells, whereas p110α-selective inhibitors had no effect. In NK cells stimulated through NKG2D, p110α inhibition modestly reduced PI3K signaling output as measured by AKT phosphorylation. Production of IFN-γ and NK cell-derived chemokines was blocked by a pan-PI3K inhibitor and partially reduced by a p110δinhibitor, with lesser effects of p110α inhibitors. Oral administration of mice with MLN1117, a p110α inhibitor in oncology clinical trials, had negligible effects on NK subset maturation or terminal subset commitment. Collectively, these results support the targeting of PIK3CA mutant tumors with selective p110α inhibitors to preserve NK cell function.
    Full-text · Article · Jun 2014 · PLoS ONE
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