Programmed Death-1 (PD-1):PD-Ligand 1 Interactions Inhibit TCR-Mediated Positive Selection of Thymocytes

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.

Tolerogenic maturation of liver sinusoidal endothelial cells promotes B7-homolog 1-dependent CD8+ T cell tolerance

“…In thymocytes, B7-H1-mediated signaling via PD-1, in combination with costimulation, down-regulates Bcl-2 and inhibits positive selection. 40 Additionally, T cell apoptosis induction by hepatocytes and hepatic stellate cells was shown to be B7-H1 dependent. 41,42 The apparent contradictory promotion of CD8 ϩ T cell survival by LSEC-derived B7-H1 signaling could be attributable to lack of costimulatory molecules on LSEC or the additional production of cytokines such as transforming growth factor beta by stellate cells.…”

B7-1 mediated costimulation regulates pancreatic autoimmunity

“…However, the numbers of CD8SP and DN thymocytes did not exhibit any significant change between the two groups (Table 1). Besides B7, B7-HI has also been suggested to play an important role in positive selection by binding its ligand PD-1 (Keir et al, 2005). We therefore asked if thymic B7-HI expression is affected in B7-1KO mice.…”

Association of an A/C single nucleotide polymorphism in programmed cell death-ligand 1 gene with Graves' disease in Japanese patients.

“…PD-1/PD-L1 interactions play a critical role in the positive selection of thymocytes while also playing a role in shaping the T-cell repertoire (35). PD-L1 is expressed on activated T cells, B cells, monocytes, dendritic cells, and on non-hematopoietic cells (35)(36)(37)(38)(39)(40)(41). PD-1-PD-L1 interaction has been suggested to play a central role in the regulation of induction and progression of autoimmune diabetes in NOD mice (42).…”

“…Programmed death-1 (PD-1; a CD28 homologue) and its ligands (PD-L1 and PD-L2; homologous to B7) constitute an inhibitory pathway of T-cell co-stimulation. PD-1/PD-L1 interactions play a critical role in the positive selection of thymocytes while also playing a role in shaping the T-cell repertoire (35). PD-L1 is expressed on activated T cells, B cells, monocytes, dendritic cells, and on non-hematopoietic cells (35)(36)(37)(38)(39)(40)(41).…”