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 7

Lack of PI3K p110δ activity prevents T cell localization into HY-mismatched skin grafts.

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Lack of PI3K p110δ activity prevents T cell localization into HY-mismatc...
C57BL/6 female mice received 3 skin grafts: one from a syngeneic male mouse (A), one from a syngeneic female mouse (B), and the third from a CBA/Ca male mouse (C). Four days following grafting, HY-specific Ab-restricted WT (PKH26-labeled) CD4+ T cells (107/mouse), were injected i.v. Graft infiltration by labeled T cells was assessed 24 hours later by wide-field fluorescence microscopy, as described in the legend to Figure 1, C and D. Original magnification, ×10. The mean values ± SD observed in samples from at least 3 animals are summarized in D. *P < 0.03 versus female and CBA/Ca graft infiltration. Parallel experiments were run in which C57BL/6 female mice engrafted with C57BL/6 male-derived skin 4 days earlier were coinjected with either WT (PKH26-labeled, red) or p110δD910A (CFSE-labeled, green) HY-specific CD4+ T cells (E and F) or with untreated (PKH26-labeled, red) or IC87114-treated (CFSE-labeled, green) HY-specific CD4+ T cells (G and H). Grafts were removed 24 hours later, and 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. The few CFSE-labeled cells are indicated by an arrowhead. Nuclei are stained by DAPI (blue). A–C show representative ×10-magnified tissue images, while the images shown in E and G were taken at a ×20 magnification. The mean T cell infiltration ± SD observed in samples from at least 3 animals is shown; *P < 0.03 (F); *P < 0.01 (H).