@article {542506,
	title = {Programmed death-1 (PD-1):PD-ligand 1 interactions inhibit TCR-mediated positive selection of thymocytes.},
	journal = {J Immunol},
	volume = {175},
	number = {11},
	year = {2005},
	month = {2005 Dec 1},
	pages = {7372-9},
	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.},
	keywords = {Animals, Antigens, CD2, Antigens, CD274, Antigens, CD28, Antigens, CD4, Antigens, CD8, Antigens, CD80, Antigens, Differentiation, Cell Differentiation, Clonal Deletion, Extracellular Signal-Regulated MAP Kinases, Flow Cytometry, Immune Tolerance, Membrane Glycoproteins, Mice, Mice, Inbred C57BL, Mice, Transgenic, Peptides, Programmed Cell Death 1 Ligand 2 Protein, Programmed Cell Death 1 Receptor, Proto-Oncogene Proteins c-bcl-2, Receptors, Antigen, T-Cell, T-Lymphocytes, Thymus Gland},
	issn = {0022-1767},
	author = {Keir, Mary E and Latchman, Yvette E and Freeman, Gordon J and Sharpe, Arlene H}
}
