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

Abstract

We have previously described critical and nonredundant roles for the phosphoinositide 3-kinase p110␦ during the activation and differentiation of naive T cells, and p110␦ 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 p110␦ activity is required for interferon-␥ production. Moreover, acute inhibition of p110␦ inhibits cytokine production and reduces hypersensitivity responses in mice. Whether p110␦ played a similar role in human T cells was unknown. Here we show that IC87114 potently blocked T-cell receptorinduced 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 p110␦ inhibition as naive T cells and show that mouse models accurately predict p110␦ function in human T cells. There is therefore a strong rationale for p110␦ inhibitors to be considered for therapeutic use in T-cell-mediated autoimmune and inflammatory diseases. (Blood. 2010;115:2203-2213)

Selective Inhibition of Phosphoinositide 3-Kinase p110α Preserves Lymphocyte Function*

“…Subsequent experiments using TCR transgenic T cells showed that p110␦ plays a more prominent role in clonal expansion of antigen-specific CD4 T cells (38). In addition, the p110␦-selective inhibitor IC87114 was reported to inhibit proliferation of both mouse and human T cells (29). An important caveat is that when present at concentrations above 1 M, IC87114 inhibits proliferation of T cells with inactive p110␦ (29).…”

“…In addition, the p110␦-selective inhibitor IC87114 was reported to inhibit proliferation of both mouse and human T cells (29). An important caveat is that when present at concentrations above 1 M, IC87114 inhibits proliferation of T cells with inactive p110␦ (29). Therefore, cellular effects of IC87114 above 1 M might result from achieving a more pan-PI3K inhibition profile.…”

“…Together these data show that 1 M concentrations of each inhibitor selectively inhibit growth and/or survival of cancer cells driven by the appropriate target, p110␣ or p110␤. Previous studies have shown that IC87114 is specific for p110␦ when cells are treated with 1 M of this compound (29). TGX-221 did not cause a significant effect in these experiments but showed a trend toward inhibiting the cell number of U87MG at 500 nM to 2 M. Based on these considerations we used a maximum concentration of 0.5-1 M of each inhibitor for most experiments.…”

“…As another means to inhibit p110␤, we used the compound MLN1316, a dual p110␣/p110␤ inhibitor that is highly selective relative to p110␦ and p110␥ (Table 1). We used IC87114 as a p110␦ inhibitor (27)(28)(29). To inhibit all class I isoforms, we used the two compounds GDC-0941 (11,30,31) and ZSTK474 (32,33).…”

PI3Kδ inhibition reduces TNF secretion and neuroinflammation in a mouse cerebral stroke model

“…We have recently shown that PI3Kd activity regulates post-Golgi transport and secretion of TNF in macrophages 18,19 . PI3Kd is similarly implicated in the release of cytokines from other immune cells [20][21][22][23][24] , and PI3Kd-selective inhibitors have significant anti-inflammatory efficacy [24][25][26] . A dual PI3Kg/d inhibitor has been shown to reduce damage in myocardial infarction 27 .…”