title: Selective inhibition of phosphoinositide 3-kinase p110α preserves lymphocyte function.
abstract: Class IA phosphoinositide 3-kinase (PI3K) is essential for clonal expansion, differentiation, and effector function of B and T lymphocytes. The p110δ catalytic isoform of PI3K is highly expressed in lymphocytes and plays a prominent role in B and T cell responses. Another class IA PI3K catalytic isoform, p110α, is a promising drug target in cancer but little is known about its function in lymphocytes. Here we used highly selective inhibitors to probe the function of p110α in lymphocyte responses in vitro and in vivo. p110α inhibition partially reduced B cell receptor (BCR)-dependent AKT activation and proliferation, and diminished survival supported by the cytokines BAFF and IL-4. Selective p110δ inhibition suppressed B cell responses much more strongly, yet maximal suppression was achieved by targeting multiple PI3K isoforms. In mouse and human T cells, inhibition of single class IA isoforms had little effect on proliferation, whereas pan-class I inhibition did suppress T cell expansion. In mice, selective p110α inhibition using the investigational agent MLN1117 (previously known as INK1117) did not disrupt the marginal zone B cell compartment and did not block T cell-dependent germinal center formation. In contrast, the selective p110δ inhibitor IC87114 strongly suppressed germinal center formation and reduced marginal zone B cell numbers, similar to a pan-class I inhibitor. These findings show that although acute p110α inhibition partially diminishes AKT activation, selective p110α inhibitors are likely to be less immunosuppressive in vivo compared with p110δ or pan-class I inhibitors.
authors.affiliation: Department of Molecular Biology & Biochemistry, and Institute for Immunology, University of California, Irvine, California 92697, USA.
authors.forename: Lomon
authors.initials: L
authors.lastname: So
authors.forename: Sung Su
authors.initials: SS
authors.lastname: Yea
authors.forename: Jean S
authors.initials: JS
authors.lastname: Oak
authors.forename: Mengrou
authors.initials: M
authors.lastname: Lu
authors.forename: Arun
authors.initials: A
authors.lastname: Manmadhan
authors.forename: Qiao Han
authors.initials: QH
authors.lastname: Ke
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Janes
authors.forename: Linda V
authors.initials: LV
authors.lastname: Kessler
authors.forename: Jeff M
authors.initials: JM
authors.lastname: Kucharski
authors.forename: Lian-Sheng
authors.initials: LS
authors.lastname: Li
authors.forename: Michael B
authors.initials: MB
authors.lastname: Martin
authors.forename: Pingda
authors.initials: P
authors.lastname: Ren
authors.forename: Katti A
authors.initials: KA
authors.lastname: Jessen
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.forename: Christian
authors.initials: C
authors.lastname: Rommel
authors.forename: David A
authors.initials: DA
authors.lastname: Fruman
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008214:Lymphocytes / Q000166:cytology* / Q000201:enzymology; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020033:Protein Isoforms; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000166:cytology / Q000201:enzymology
chemical_list: D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020033:Protein Isoforms; D058543:Class Ia Phosphatidylinositol 3-Kinase; D002118:Calcium