PI3K p110delta regulates T-cell cytokine production during primary and secondary immune responses in mice and humans.
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.
Soond
Dalya R
DR
Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge, United Kingdom.
Bjørgo
Elisa
E
Moltu
Kristine
K
Dale
Verity Q
VQ
Patton
Daniel T
DT
Torgersen
Knut Martin
KM
Galleway
Fiona
F
Twomey
Breda
B
Clark
Jonathan
J
Gaston
J S Hill
JS
Taskén
Kjetil
K
Bunyard
Peter
P
Okkenhaug
Klaus
K
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001168:Arthritis / Q000201:enzymology / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D058534:Class I Phosphatidylinositol 3-Kinases; D016207:Cytokines / Q000096:biosynthesis*; D006801:Humans; D006967:Hypersensitivity / Q000201:enzymology / Q000276:immunology; D007109:Immunity / Q000187:drug effects / Q000276:immunology*; D007156:Immunologic Memory / Q000187:drug effects / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011799:Quinazolines / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D000225:Adenine; D058534:Class I Phosphatidylinositol 3-Kinases; D016207:Cytokines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011799:Quinazolines; D011948:Receptors, Antigen, T-Cell; C477872:IC 87114; C509622:1-phosphatidylinositol 3-kinase p110 subunit, mouse; C486018:PIK3CD protein, human