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Abstract

Activated T cells must mediate effector responses sufficient 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 PD-1 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 a mechanism involving T cell recruitment, transient activation, and rapid desensitization, allowing the T cell response to rapidly adjust to changes in antigen presentation and minimize collateral injury to the host.