T cell receptor–induced phosphoinositide-3-kinase p110δ activity is required for T cell localization to antigenic tissue in mice
Sarah J. Jarmin, … , Klaus Okkenhaug, Federica M. Marelli-Berg
Sarah J. Jarmin, … , Klaus Okkenhaug, Federica M. Marelli-Berg
Published February 7, 2008
Citation Information: J Clin Invest. 2008;118(3):1154-1164. https://doi.org/10.1172/JCI33267.
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Research Article Immunology

T cell receptor–induced phosphoinositide-3-kinase p110δ 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 p110δ contributed to the regulation of these events. T lymphocytes from mice expressing catalytically inactive p110δ 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 p110δ activity. These observations suggest that pharmacological targeting of p110δ activity is a viable strategy for the therapy of T cell–mediated pathology.

Authors

Sarah J. Jarmin, Rachel David, Liang Ma, Jan-Guo Chai, Hamlata Dewchand, Aya Takesono, Anne J. Ridley, Klaus Okkenhaug, Federica M. Marelli-Berg

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Figure 1

PI3K P110δ does not contribute to constitutive T cell migration.

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PI3K P110δ does not contribute to constitutive T cell migration. (A) HY-...
(A) HY-specific H2-Ab–restricted WT and P110δD910A T cells (5 × 105/well) were seeded onto untreated syngeneic female-derived EC monolayers grown on 3-μm-pore Transwells, and T cell migration was monitored as described in Methods. Results are expressed as a percentage of migrated T cells at the given time points and reported as the average of 3 experiments of identical design. Error bars are shown. (B) HY-specific H2-Ab–restricted WT and P110δD910A T cells (5 × 105/well) were seeded onto ICAM-1–coated (2 μg/ml) 35-mm dishes, and their migration was observed for 25–30 minutes by time-lapse microscopy. A representative example of a series of 3 independent experiments with similar design is shown. Mean migration speed ± SEM is shown. (C and D) PKH26-labeled HY-specific H2-Ab–restricted CD4+ WT and P110δD910A T cells were injected i.v. into syngeneic female mice. T cell localization in the indicated tissues was assessed 24 hours later by wide-field fluorescence microscopy. To minimize the effect of arbitrary choice of field, tissue infiltration was quantified by randomly selecting ten ×10-magnified fields from tissue samples from at least 3 animals and assessing the number of fluorescent cells in each field. Each panel shows a representative tissue image. The mean T cell infiltration ± SD observed in samples from at least 3 animals is shown in D.