{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T03:03:56Z","timestamp":1791428636179,"version":"4.3.3"},"reference-count":56,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2019,3,1]],"date-time":"2019-03-01T00:00:00Z","timestamp":1551398400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>In chronic lymphocytic leukemia (CLL), signaling through several prosurvival B cell surface receptors activates the PI3K signaling pathway. Idelalisib is a highly selective PI3K (PI3K\u03b4) isoform-specific inhibitor effective in relapsed\/refractory CLL and follicular lymphoma. However, severe autoimmune adverse effects in association with the use of idelalisib in the treatment of CLL, particularly as a first-line therapy, gave indications that idelalisib may preferentially target the suppressive function of regulatory T cells (Tregs). On this background, we examined the effect of idelalisib on the function of human Tregs ex vivo with respect to proliferation, TCR signaling, phenotype, and suppressive function. Our results show that human Tregs are highly susceptible to PI3K\u03b4 inactivation using idelalisib compared with CD4+ and CD8+ effector T cells (Teffs) as evident from effects on anti-CD3\/CD28\/CD2\u2013induced proliferation (order of susceptibility [IC50]: Treg [.5 \u03bcM] &amp;gt; CD4+ Teff [2.0 \u03bcM] &amp;gt; CD8+ Teff [6.5 \u03bcM]) and acting at the level of AKT and NF-\u03baB phosphorylation. Moreover, idelalisib treatment of Tregs altered their phenotype and reduced their suppressive function against CD4+ and CD8+ Teffs. Phenotyping Tregs from CLL patients treated with idelalisib supported our in vitro findings. Collectively, our data show that human Tregs are more dependent on PI3K\u03b4-mediated signaling compared with CD4+ and CD8+ Teffs. This Treg-preferential effect could explain why idelalisib produces adverse autoimmune effects by breaking Treg-mediated tolerance. However, balancing effects on Treg sensitivity versus CD8+ Teff insensitivity to idelalisib could still potentially be exploited to enhance inherent antitumor immune responses in patients.<\/jats:p>","DOI":"10.4049\/jimmunol.1701703","type":"journal-article","created":{"date-parts":[[2019,1,28]],"date-time":"2019-01-28T14:50:14Z","timestamp":1548687014000},"page":"1397-1405","source":"Crossref","is-referenced-by-count":126,"title":["The PI3K p110\u03b4 Isoform Inhibitor Idelalisib Preferentially Inhibits Human Regulatory T Cell Function"],"prefix":"10.1093","volume":"202","author":[{"given":"Stalin","family":"Chellappa","sequence":"first","affiliation":[{"name":"Department for Cancer Immunology, Institute for Cancer Research, Oslo University Hospital , N-0424 Oslo ,","place":["Norway"]},{"name":"K.G. Jebsen Centre for B Cell Malignancies, Institute for Clinical Medicine, University of Oslo , N-0424 Oslo ,","place":["Norway"]},{"name":"K.G. Jebsen Centre for Cancer Immunotherapy, Institute for Clinical Medicine, University of Oslo , N-0424 Oslo ,","place":["Norway"]},{"name":"Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo , N-0318 Oslo ,","place":["Norway"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2380-6309","authenticated-orcid":false,"given":"Kushi","family":"Kushekhar","sequence":"additional","affiliation":[{"name":"Department for Cancer Immunology, Institute for Cancer Research, Oslo University Hospital , N-0424 Oslo ,","place":["Norway"]},{"name":"K.G. Jebsen Centre for B Cell Malignancies, Institute for Clinical Medicine, University of Oslo , N-0424 Oslo ,","place":["Norway"]},{"name":"K.G. Jebsen Centre for Cancer Immunotherapy, Institute for Clinical Medicine, University of Oslo , N-0424 Oslo ,","place":["Norway"]},{"name":"Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo , N-0318 Oslo ,","place":["Norway"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ludvig A","family":"Munthe","sequence":"additional","affiliation":[{"name":"K.G. Jebsen Centre for B Cell Malignancies, Institute for Clinical Medicine, University of Oslo , N-0424 Oslo ,","place":["Norway"]},{"name":"Department of Immunology and Transfusion Medicine, Oslo University Hospital , N-0424 Oslo ,","place":["Norway"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geir E","family":"Tj\u00f8nnfjord","sequence":"additional","affiliation":[{"name":"K.G. Jebsen Centre for B Cell Malignancies, Institute for Clinical Medicine, University of Oslo , N-0424 Oslo ,","place":["Norway"]},{"name":"Department of Haematology, Oslo University Hospital , N-0424 Oslo ,","place":["Norway"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0115-8382","authenticated-orcid":false,"given":"Einar M","family":"Aandahl","sequence":"additional","affiliation":[{"name":"Department for Cancer Immunology, Institute for Cancer Research, Oslo University Hospital , N-0424 Oslo ,","place":["Norway"]},{"name":"K.G. Jebsen Centre for B Cell Malignancies, Institute for Clinical Medicine, University of Oslo , N-0424 Oslo ,","place":["Norway"]},{"name":"K.G. Jebsen Centre for Cancer Immunotherapy, Institute for Clinical Medicine, University of Oslo , N-0424 Oslo ,","place":["Norway"]},{"name":"Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo , N-0318 Oslo ,","place":["Norway"]},{"name":"Section for Transplantation Surgery, Oslo University Hospital , N-0424 Oslo ,","place":["Norway"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9432-4051","authenticated-orcid":false,"given":"Klaus","family":"Okkenhaug","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Cambridge , Cambridge CB2 1QP ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kjetil","family":"Task\u00e9n","sequence":"additional","affiliation":[{"name":"Department for Cancer Immunology, Institute for Cancer Research, Oslo University Hospital , N-0424 Oslo ,","place":["Norway"]},{"name":"K.G. Jebsen Centre for B Cell Malignancies, Institute for Clinical Medicine, University of Oslo , N-0424 Oslo ,","place":["Norway"]},{"name":"K.G. Jebsen Centre for Cancer Immunotherapy, Institute for Clinical Medicine, University of Oslo , N-0424 Oslo ,","place":["Norway"]},{"name":"Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo , N-0318 Oslo ,","place":["Norway"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,3,1]]},"reference":[{"key":"2025030417560818100_r1","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1038\/nri2785","article-title":"FOXP3+ regulatory T cells in the human immune system","volume":"10","author":"Sakaguchi","year":"2010","journal-title":"Nat. Rev. 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