Abstract
Positive selection during thymocyte development is driven by the affinity and avidity of the TCR for MHC-peptide complexes expressed in the thymus. In this study, we show that programmed death-1 (PD-1), a member of the B7/CD28 family of costimulatory receptors, inhibits TCR-mediated positive selection through PD-1 ligand 1 (PD-L1):PD-1 interactions. Transgenic mice that constitutively overexpress PD-1 on CD4+CD8+ thymocytes display defects in positive selection in vivo. Using an in vitro model system, we find that PD-1 is up-regulated following TCR engagement on CD4+CD8+ murine thymocytes. Coligation of TCR and PD-1 on CD4+CD8+ thymocytes with a novel PD-1 agonistic mAb inhibits the activation of ERK and up-regulation of bcl-2, both of which are downstream mediators essential for positive selection. Inhibitory signals through PD-1 can overcome the ability of positive costimulators, such as CD2 and CD28, to facilitate positive selection. Finally, defects in positive selection that result from PD-1 overexpression in thymocytes resolve upon elimination of PD-L1, but not PD-1 ligand 2, expression. PD-L1-deficient mice have increased numbers of CD4+CD8+ and CD4+ thymocytes, indicating that PD-L1 is involved in normal thymic selection. These data demonstrate that PD-1:PD-L1 interactions are critical to positive selection and play a role in shaping the T cell repertoire.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, Differentiation / immunology*
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Antigens, Differentiation / metabolism
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B7-1 Antigen / immunology*
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B7-1 Antigen / metabolism
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B7-H1 Antigen
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CD2 Antigens / immunology
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CD2 Antigens / metabolism
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CD28 Antigens / immunology
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CD28 Antigens / metabolism
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CD4 Antigens / immunology
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CD4 Antigens / metabolism
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CD8 Antigens / immunology
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CD8 Antigens / metabolism
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Cell Differentiation / immunology*
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Clonal Deletion / immunology
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Flow Cytometry
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Immune Tolerance / immunology*
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Membrane Glycoproteins / immunology*
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Membrane Glycoproteins / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Peptides / immunology*
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Peptides / metabolism
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Programmed Cell Death 1 Ligand 2 Protein
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Programmed Cell Death 1 Receptor
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Receptors, Antigen, T-Cell / immunology*
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Receptors, Antigen, T-Cell / metabolism
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T-Lymphocytes / cytology
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T-Lymphocytes / immunology*
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T-Lymphocytes / metabolism
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Thymus Gland / cytology
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Thymus Gland / growth & development
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Thymus Gland / immunology
Substances
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Antigens, Differentiation
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B7-1 Antigen
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B7-H1 Antigen
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CD2 Antigens
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CD28 Antigens
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CD4 Antigens
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CD8 Antigens
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Cd274 protein, mouse
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Membrane Glycoproteins
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Pdcd1 protein, mouse
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Pdcd1lg2 protein, mouse
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Peptides
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Programmed Cell Death 1 Ligand 2 Protein
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Programmed Cell Death 1 Receptor
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Proto-Oncogene Proteins c-bcl-2
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Receptors, Antigen, T-Cell
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Extracellular Signal-Regulated MAP Kinases