Interactions between programmed death-1 and programmed death ligand-1 promote tolerance by blocking the T cell receptor-induced stop signal

By B. Fife, Kristen E. Pauken, T. Eagar, T. Obu, Jenny Wu, Q. Tang, M. Azuma, M. Krummel, J. Bluestone. Nature Immunology, 2009

653 citations recorded by the source corpus.

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.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/1c3d965d596f2d6027e6fed4e94e8e1ee3a3fa2a

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Citations in the corpus

Macrophages impede CD8 T cells from reaching tumor cells and limit the efficacy of anti–PD-1 treatment (2018, background): “During acute immune responses, the expression of PD-1 at the surface of activated T cells inhibits the formation of a stable antigen-dependent contact with the antigen-presenting cells (40, 41).”
The PD-1 Pathway in Tolerance and Autoimmunity (2010, background): “(140) reported that PD-1 ligation affects the stability of DC-T-cell contacts by inhibiting TCR-induced stop signals.”
Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1. (2011, positive): “Despite providing a benefit in these settings, TH17 can play a pathologic role in the induction of several autoimmune diseases, including collagen-induced arthritis, experimental autoimmune encephalomyelitis (EAE), inflammatory bowel diseases (Fife et al., 2009; Weaver et al., 2007; Wu et al., 2009)”
PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors (2010, background): “Also, both PD-1/PD-L1 and CTLA-4/B7 interactions help to maintain peripheral tolerance through modifications in T-cell motility; however, they seem to do so through distinct mechanisms (11, 12).”
The blockade of immune checkpoints in cancer immunotherapy (2012, background): “Also, because PD1 engagement inhibits the TCR 'stop signal', this pathway could modify the duration of T cell–APC or T cell–target cell contac”