Immunity
Volume 40, Issue 2, 20 February 2014, Pages 235-247
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Article
Tuning of Antigen Sensitivity by T Cell Receptor-Dependent Negative Feedback Controls T Cell Effector Function in Inflamed Tissues

https://doi.org/10.1016/j.immuni.2013.11.017Get rights and content
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Highlights

  • Effector CD4+ T cell function and motility inversely correlate in inflamed tissue

  • Antigen sensitivity tuning limits the duration of effector T cell activity in vivo

  • PD-1 upregulation contributes to sensitivity loss and cessation of effector function

  • Feedback regulation of effector activity helps balance host defense and tissue damage

Summary

Activated T cells must mediate effector responses sufficiently to clear pathogens while avoiding excessive tissue damage. Here we have combined dynamic intravital microscopy with ex vivo assessments of T cell cytokine responses to generate a detailed spatiotemporal picture of CD4+ T cell effector regulation in the skin. In response to antigen, effector T cells arrested transiently on antigen-presenting cells, briefly producing cytokine and then resuming migration. Antigen recognition led to upregulation of the programmed death-1 (PD-1) glycoprotein by T cells and blocking its canonical ligand, programmed death-ligand 1 (PD-L1), lengthened the duration of migration arrest and cytokine production, showing that PD-1 interaction with PD-L1 is a major negative feedback regulator of antigen responsiveness. We speculate that the immune system employs T cell recruitment, transient activation, and rapid desensitization to allow the T cell response to rapidly adjust to changes in antigen presentation and minimize collateral injury to the host.

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These authors contributed equally to this work

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Present address: Genentech, 1 DNA Way, MS34, South San Francisco, CA 94080, USA