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 2

PI3K p110δ is not required for chemokine-induced T cell migration.

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PI3K p110δ is not required for chemokine-induced T cell migration. (A an...
(A and B) HY-specific H2-Ab–restricted WT and P110δD910A CD4+ T cells (5 × 105/well) were exposed to CXCL10 (300 ng/ml; filled symbols, A and D), CXCL12 (50 ng/ml; filled symbols, B and E), or CCL5 (100 ng/ml; filled symbols, C and F) through 5-μm-pore Transwells. In the experiments analyzing migratory responses to CXCL12, T cells were stimulated with plastic-bound anti-CD3 (1 μg/ml) and anti-CD28 (5 μg/ml) for 72 hours to induce CXCR4 expression. Spontaneous migration in chemotaxis medium (RPMI 0.5% FCS) alone was also measured (open symbols). The number of migrated T cells was monitored at the indicated time points. Results are expressed as the percentage of input T lymphocytes that had migrated through the filters at any given time point and represent the mean of at least 3 independent experiments ± SEM. *P < 0.05 at all time points except 2 hours (B, C, and E) and 24 hours. (G–J) C57BL/6 female mice received an i.p. injection of CXCL10 (1,200 ng). One hour later, PKH26-labeled HY-specific H2-Ab–restricted WT and P110δD910A T cells (5 × 105/well) T cells were injected i.v. After 6 hours, localization of PKH26-labeled T cells in the peritoneal cavity was assessed by flow cytometry. The panels (representative of 1 experiment) show the number of PKH26-labeled T cells in the CD4-gated T cell population. The mean T cell numbers ± SEM observed in samples from at least 3 animals are summarized in K. *P < 0.02.