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Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR-induced stop signal.

ABSTRACT: Programmed death 1 (PD-1) is an inhibitory molecule expressed on activated T cells; however, the biological context in which PD-1 controls T cell tolerance remains unclear. Using two-photon laser-scanning microscopy, we show here that unlike naive or activated islet antigen-specific T cells, tolerized islet antigen-specific T cells moved freely and did not swarm around antigen-bearing dendritic cells (DCs) in pancreatic lymph nodes. Inhibition of T cell antigen receptor (TCR)-driven stop signals depended on continued interactions between PD-1 and its ligand, PD-L1, as antibody blockade of PD-1 or PD-L1 resulted in lower T cell motility, enhanced T cell-DC contacts and caused autoimmune diabetes. Blockade of the immunomodulatory receptor CTLA-4 did not alter T cell motility or abrogate tolerance. Thus, PD-1-PD-L1 interactions maintain peripheral tolerance by mechanisms fundamentally distinct from those of CTLA-4.

SUBMITTER: Fife BT 

PROVIDER: S-EPMC2778301 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR-induced stop signal.

Fife Brian T BT   Pauken Kristen E KE   Eagar Todd N TN   Obu Takashi T   Wu Jenny J   Tang Qizhi Q   Azuma Miyuki M   Krummel Matthew F MF   Bluestone Jeffrey A JA  

Nature immunology 20090927 11

Programmed death 1 (PD-1) is an inhibitory molecule expressed on activated T cells; however, the biological context in which PD-1 controls T cell tolerance remains unclear. Using two-photon laser-scanning microscopy, we show here that unlike naive or activated islet antigen-specific T cells, tolerized islet antigen-specific T cells moved freely and did not swarm around antigen-bearing dendritic cells (DCs) in pancreatic lymph nodes. Inhibition of T cell antigen receptor (TCR)-driven stop signals  ...[more]

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