T cell receptor-induced phosphoinositide-3-kinase p110delta activity is required for T cell localization to antigenic tissue in mice.
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.
Jarmin
Sarah J
SJ
Department of Immunology, Division of Medicine, Imperial College London, Hammersmith Campus, London, United Kingdom.
David
Rachel
R
Ma
Liang
L
Chai
Jan-Guo
JG
Dewchand
Hamlata
H
Takesono
Aya
A
Ridley
Anne J
AJ
Okkenhaug
Klaus
K
Marelli-Berg
Federica M
FM
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*
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