Programmed death-1 (PD-1): PD-ligand 1 interactions inhibit TCR-mediated positive selection of thymocytes

ME Keir, YE Latchman, GJ Freeman… - The Journal of …, 2005 - journals.aai.org
ME Keir, YE Latchman, GJ Freeman, AH Sharpe
The Journal of Immunology, 2005journals.aai.org
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 …
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.
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