title: T cell receptor-induced phosphoinositide-3-kinase p110delta activity is required for T cell localization to antigenic tissue in mice.
abstract: The establishment of T cell-mediated inflammation requires the migration of primed T lymphocytes from the blood stream and their retention in antigenic sites. While naive T lymphocyte recirculation in the lymph and blood is constitutively regulated and occurs in the absence of inflammation, the recruitment of primed T cells to nonlymphoid tissue and their retention at the site are enhanced by various inflammatory signals, including TCR engagement by antigen-displaying endothelium and resident antigen-presenting cells. In this study, we investigated whether signals downstream of TCR ligation mediated by the phosphoinositide-3-kinase (PI3K) subunit p110delta contributed to the regulation of these events. T lymphocytes from mice expressing catalytically inactive p110delta displayed normal constitutive trafficking and migratory responses to nonspecific stimuli. However, these cells lost susceptibility to TCR-induced migration and failed to localize efficiently to antigenic tissue. Importantly, we showed that antigen-induced T cell trafficking and subsequent inflammation was abrogated by selective pharmacological inhibition of PI3K p110delta activity. These observations suggest that pharmacological targeting of p110delta activity is a viable strategy for the therapy of T cell-mediated pathology.
authors.affiliation: Department of Immunology, Division of Medicine, Imperial College London, Hammersmith Campus, London, United Kingdom.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Jarmin
authors.forename: Rachel
authors.initials: R
authors.lastname: David
authors.forename: Liang
authors.initials: L
authors.lastname: Ma
authors.forename: Jan-Guo
authors.initials: JG
authors.lastname: Chai
authors.forename: Hamlata
authors.initials: H
authors.lastname: Dewchand
authors.forename: Aya
authors.initials: A
authors.lastname: Takesono
authors.forename: Anne J
authors.initials: AJ
authors.lastname: Ridley
authors.forename: Klaus
authors.initials: K
authors.lastname: Okkenhaug
authors.forename: Federica M
authors.initials: FM
authors.lastname: Marelli-Berg
mesh_terms: D000818:Animals; D018106:CD28 Antigens / Q000502:physiology; D002465:Cell Movement; D002634:Chemotaxis, Leukocyte; D058534:Class I Phosphatidylinositol 3-Kinases; D006182:H-Y Antigen / Q000276:immunology; D007371:Interferon-gamma / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D015398:Signal Transduction; D016038:Skin Transplantation; D013601:T-Lymphocytes / Q000502:physiology*
chemical_list: D018106:CD28 Antigens; D058534:Class I Phosphatidylinositol 3-Kinases; D006182:H-Y Antigen; D007371:Interferon-gamma; D019869:Phosphatidylinositol 3-Kinases; D011948:Receptors, Antigen, T-Cell; C421683:Pik3cd protein, mouse