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

Brian T. Fife, Kristen E. Pauken, Todd N. Eagar, Takashi Obu, Jenny Wu, Qizhi Tang, Miyuki Azuma, Matthew F. Krummel, Jeffrey A. Bluestone

Research output: Contribution to journalArticle

414 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1185-1192
Number of pages8
JournalNature Immunology
Volume10
Issue number11
DOIs
StatePublished - Nov 2009

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T-Cell Antigen Receptor
T-Lymphocytes
Antigens
Dendritic Cells
Cell Movement
Peripheral Tolerance
Type 1 Diabetes Mellitus
Photons
Confocal Microscopy
Lymph Nodes
Ligands
Antibodies

ASJC Scopus subject areas

  • Immunology

Cite this

Fife, B. T., Pauken, K. E., Eagar, T. N., Obu, T., Wu, J., Tang, Q., ... Bluestone, J. A. (2009). Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR-induced stop signal. Nature Immunology, 10(11), 1185-1192. https://doi.org/10.1038/ni.1790

Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR-induced stop signal. / Fife, Brian T.; Pauken, Kristen E.; Eagar, Todd N.; Obu, Takashi; Wu, Jenny; Tang, Qizhi; Azuma, Miyuki; Krummel, Matthew F.; Bluestone, Jeffrey A.

In: Nature Immunology, Vol. 10, No. 11, 11.2009, p. 1185-1192.

Research output: Contribution to journalArticle

Fife, BT, Pauken, KE, Eagar, TN, Obu, T, Wu, J, Tang, Q, Azuma, M, Krummel, MF & Bluestone, JA 2009, 'Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR-induced stop signal.', Nature Immunology, vol. 10, no. 11, pp. 1185-1192. https://doi.org/10.1038/ni.1790
Fife, Brian T. ; Pauken, Kristen E. ; Eagar, Todd N. ; Obu, Takashi ; Wu, Jenny ; Tang, Qizhi ; Azuma, Miyuki ; Krummel, Matthew F. ; Bluestone, Jeffrey A. / Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR-induced stop signal. In: Nature Immunology. 2009 ; Vol. 10, No. 11. pp. 1185-1192.
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