title: The p85alpha regulatory subunit of class IA phosphoinositide 3-kinase regulates beta-selection in thymocyte development.
abstract: We examined the role of class IA PI3K in pre-TCR controlled beta-selection and TCR-controlled positive/negative selection in thymic development. Using mice deficient for p85alpha, a major regulatory subunit of the class IA PI3K family, the role of class IA PI3K in beta-selection was examined by injection of anti-CD3epsilon mAb into p85alpha(-/-)Rag-2(-/-) mice, which mimics pre-TCR signals. Transition of CD4(-)CD8(-) double-negative (DN) to CD4(+)CD8(+) double-positive (DP) thymocytes triggered by anti-CD3epsilon mAb was significantly impaired in p85alpha(-/-)Rag-2(-/-) compared with p85alpha(+/-)Rag-2(-/-) mice. Furthermore, DP cell numbers were lower in p85alpha(-/-)DO11.10/Rag-2(-/-) TCR-transgenic mice than in DO11.10/Rag-2(-/-) mice. In addition, inhibition by IC87114 of the major class IA PI3K catalytic subunit expressed in lymphocytes, p110delta, blocked transition of DN to DP cells in embryonic day 14.5 fetal thymic organ culture without affecting cell viability. In the absence of phosphatase and tensin homolog deleted on chromosome 10, where class IA PI3K signals would be amplified, the DN to DP transition was accelerated. In contrast, neither positive nor negative selection in Rag-2(-/-)TCR-transgenic mice was perturbed by the lack of p85alpha. These findings establish an important function of class IA PI3K in the pre-TCR-controlled developmental transition of DN to DP thymocytes.
authors.affiliation: Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Fumiko
authors.initials: F
authors.lastname: Shiroki
authors.forename: Satoshi
authors.initials: S
authors.lastname: Matsuda
authors.forename: Tomomitsu
authors.initials: T
authors.lastname: Doi
authors.forename: Mari
authors.initials: M
authors.lastname: Fujiwara
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Mochizuki
authors.forename: Takashi
authors.initials: T
authors.lastname: Kadowaki
authors.forename: Harumi
authors.initials: H
authors.lastname: Suzuki
authors.forename: Shigeo
authors.initials: S
authors.lastname: Koyasu
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes; D018414:CD8-Positive T-Lymphocytes; D002470:Cell Survival; D004622:Embryo, Mammalian; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D019869:Phosphatidylinositol 3-Kinases / Q000172:deficiency / Q000502:physiology*; D021122:Protein Subunits; D011948:Receptors, Antigen, T-Cell; D016693:Receptors, Antigen, T-Cell, alpha-beta; D013950:Thymus Gland / Q000166:cytology* / Q000196:embryology / Q000254:growth & development
chemical_list: D021122:Protein Subunits; D011948:Receptors, Antigen, T-Cell; D016693:Receptors, Antigen, T-Cell, alpha-beta; D019869:Phosphatidylinositol 3-Kinases